(2-aryloxyacetylamino)phenylpropionic acid derivatives, processes for preparation thereof and use thereof as medicaments

ABSTRACT

The invention relates to substituted (2-aryloxyacetylamino)phenylpropionic acid derivatives, and to the physiologically acceptable salts thereof. 
     The invention relates to compounds of the formula I 
                         
in which R1, R2, R3, R4, R5, R6, R7, R8, R9 and A are each defined as specified, and the physiologically compatible salts thereof. The compounds are suitable, for example, for treatment of diabetes.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No.61/422,777 filed on Dec. 14, 2010.

The invention relates to substituted(2-aryloxyacetylamino)phenylpropionic acid derivatives, and to thephysiologically acceptable salts thereof.

Structurally similar compounds have already been described in the priorart (see Eisai WO2002/100812), as has the use thereof as PPAR agonistsor antagonists.

It was an object of the invention to provide compounds which display atherapeutically utilizable action. It was a further object to find novelcompounds suitable for treatment of hyperglycemia and of diabetes. Itwas a further object to find novel compounds which activate the GPR40receptor and are thus suitable for treatment of hyperglycemia and ofdiabetes.

The invention therefore relates to compounds of the formula I

in which

-   R1 is O—(C₁-C₆)-alkyl, O—(C₃-C₆)-cycloalkyl,    O—(C₁-C₃)-alkylene-(C₃-C₆)-cycloalkyl, —(C₂-C₆)-alkynyl or CN, where    the O—(C₁-C₆)-alkyl radical, the O—(C₃-C₆)-cycloalkyl, the    O—(C₁-C₃)-alkylene-(C₃-C₆)-cycloalkyl and the (C₂-C₆)-alkynyl    radical may be mono- or polysubstituted by F;-   R2, R9 is H, F, Cl, Br, CN, CH₃, CO—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl or    O—(C₁-C₆)-alkyl, where the CO—(C₁-C₆)-alkyl radical, the    (C₁-C₆)-alkyl radical and the O—(C₁-C₆)-alkyl radical may each be    mono- or polysubstituted by F;-   R3 is H, (C₁-C₆)-alkyl, (C₁-C₃)-alkylene-(C₃-C₆)-cycloalkyl or    (C₃-C₆)-cycloalkyl;-   R4 is (C₁-C₆)-alkyl, (C₁-C₃)-alkylene-(C₃-C₆)-cycloalkyl or    (C₃-C₆)-cycloalkyl;-   R5, R6, R7 are each independently H, F, Cl, Br, I, NO₂, ON,    O—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, (C₁-C₃)-alkylene-(C₃-C₆)-cycloalkyl,    NH₂, NH(C₁-C₆)-alkyl, N((C₁-C₆)-alkyl)₂, SO₂—CH₃, SO₂—NH₂,    SO₂—NH(C₁-C₆)-alkyl, SO₂—N((C₁-C₆)-alkyl)₂, COOH, COO—(C₁-C₆)-alkyl,    CONH₂, CONH(C₁-C₆)-alkyl, CON((C₁-C₆)-alkyl)₂, SF₅, (C₆-C₁₀)-aryl,    (C₃-C₁₀)-cycloalkyl, or a 4- to 12-membered heterocycle, where the    (C₁-C₆)-alkyl radical and the O—(C₁-C₆)-alkyl radical may be mono-    or polysubstituted by F and where the (C₆-C₁₀)-aryl radical, the    (C₃-C₁₀)-cycloalkyl radical and the 4- to 12-membered heterocycle    radical may each be mono- to trisubstituted by    -   F, Cl, Br, I, OH, CF₃, CHF₂, CH₂F, NO₂, CN, OCF₃, OCHF₂,        O—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, NH₂, NH(C₁-C₆)-alkyl,        N((C₁-C₆)-alkyl)₂, SO₂—CH₃, SO₂—NH₂, SO₂—NH(C₁-C₆)-alkyl,        SO₂—N((C₁-C₆)-alkyl)₂, COOH, COO—(C₁-C₆)-alkyl, CONH₂,        CONH(C₁-C₆)-alkyl, CON((C₁-C₆)-alkyl)₂ or SF₅;-   R8 is H or (C₁-C₆)-alkyl;-   A is (C₆-C₁₀)-aryl or a 4- to 12-membered heterocycle;-   and physiologically compatible salts thereof.

A further embodiment relates to compounds of the formula I in which oneor more radicals have the following definitions:

-   R1 is O—(C₁-C₆)-alkyl, O—(C₃-C₆)-cycloalkyl,    O—(C₁-C₃)-alkylene-(C₃-C₃)-cycloalkyl, —(C₂-C₆)-alkynyl or CN, where    the O—(C₁-C₆)-alkyl radical, the O—-(C₃-C₆)-cycloalkyl, the    O—(C₁-C₃)-alkylene-(C₃-C₆)-cycloalkyl and the (C₂-C₆)-alkynyl    radical may be mono- or polysubstituted by F;-   R2, R9 is H, F, Cl, Br, CN, CH₃, CO—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl or    O—(C₁-C₆)-alkyl, where the CO—(C₁-C₆)-alkyl radical, the    (C₁-C₆)-alkyl radical and the O—(C₁-C₆)-alkyl radical may each be    mono- or polysubstituted by F;-   R3 is H, (C₁-C₆)-alkyl, (C₁-C₃)-alkylene-(C₃-C₆)-cycloalkyl or    (C₃-C₆)-cycloalkyl;-   R4 is (C₁-C₆)-alkyl, (C₁-C₃)-alkylene-(C₃-C₆)-cycloalkyl or    (C₃-C₆)-cycloalkyl;-   R5, R6, R7 are each independently H, F, Cl, Br, I, CN,    O—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, SF₅ or phenyl, where the    (C₁-C₆)-alkyl radical and the O—(C₁-C₆)-alkyl radical may each be    mono- or polysubstituted by F;-   R8 is H or (C₁-C₆)-alkyl;-   A is phenyl or a 6-membered heterocycle;    and physiologically compatible salts thereof.

A further embodiment relates to compounds of the formula I in which oneor more radicals have the following definitions:

-   R1 is O—(C₁-C₆)-alkyl or —(C₂-C₆)-alkynyl, where the O—(C₁-C₆)-alkyl    radical and the (C₂-C₆)-alkynyl radical may be mono- or    polysubstituted by F;-   R2, R9 is H;-   R3 is H, (C₁-C₆)-alkyl, (C₁-C₃)-alkylene-(C₃-C₆)-cycloalkyl or    (C₃-C₆)-cycloalkyl;-   R4 is (C₁-C₆)-alkyl, (C₁-C₃)-alkylene-(C₃-C₆)-cycloalkyl or    (C₃-C₆)-cycloalkyl;-   R5, R6, R7 are each independently H, Cl, Br, CH₃ or (C₁-C₆)-alkyl,    where the (C₁-C₆)-alkyl radical may be mono- or polysubstituted by    F;-   R8 is H;-   A is phenyl or pyridyl;    and physiologically compatible salts thereof.

A further embodiment relates to compounds of the formula I in which oneor more radicals have the following definitions:

-   R1 is O—(C₁-C₆)-alkyl or (C₂-C₆)-alkynyl;-   R2, R9 is H;-   R3 is H, (C₁-C₆)-alkyl;-   R4 is (C₁-C₆)-alkyl, (C₁-C₃)-alkylene-(C₃-C₆)-cycloalkyl or    (C₃-C₆)-cycloalkyl,-   R5, R6, R7 are each independently H, Cl, Br, CH₃ or (C₁-C₆)-alkyl,    where the (C₁-C₆)-alkyl radical may be mono- or polysubstituted by    F;-   R8 is H;-   A is phenyl;    and physiologically compatible salts thereof.

A further embodiment relates to compounds of the formula I in which oneor more radicals have the following definitions:

-   R1 is O—(C₁-C₆)-alkyl or (C₂-C₆)-alkynyl;-   R2, R9 is H;-   R3 is H or (C₁-C₆)-alkyl;-   R4 is (C₁-C₆)-alkyl, (C₁-C₃)-alkylene-(C₃-C₆)-cycloalkyl or    (C₃-C₆)-cycloalkyl;-   R5, R6, R7 are each independently H, Cl, Br, CH₃ or (C₁-C₆)-alkyl,    where the (C₁-C₆)-alkyl radical may be mono- or polysubstituted by    F;-   R8 is H;-   A is pyridyl;    and physiologically compatible salts thereof.

If radicals or substituents can occur more than once in the compounds ofthe formula I, they may each independently be defined as specified andbe the same or different.

The alkyl and alkynyl radicals in the R1, R2, R3, R4, R5, R6, R7, R8 andR9 radicals may be either straight-chain or branched.

The invention relates to compounds of the formula I in the form of thesalts, racemates, racemic mixtures and pure enantiomers thereof, and ofthe diastereomers and mixtures thereof.

The invention further provides both stereoisomer mixtures of the formulaI and the pure stereoisomers of the formula I, and also diastereomermixtures of the formula I and the pure diastereomers. The mixtures areseparated, for example, by a chromatographic route.

The present invention encompasses all possible tautomeric forms of thecompounds of the formula I.

Owing to their higher water solubility compared to the starting or basecompounds, pharmaceutically acceptable salts are particularly suitablefor medical applications. These salts must have a pharmaceuticallyacceptable anion or cation.

Salts with a pharmaceutically unacceptable anion likewise form part ofthe scope of the invention as useful intermediates for the preparationor purification of pharmaceutically acceptable salts and/or for use innontherapeutic, for example in vitro, applications.

The compounds of the invention may also exist in various polymorphousforms, for example as amorphous and crystalline polymorphous forms. Allpolymorphous forms of the compounds of the invention belong within theframework of the invention and are a further aspect of the invention.

All references to “compound(s) of formula I” hereinafter refer tocompound(s) of the formula I as described above, and the salts andsolvates thereof, as described herein.

An alkyl radical is understood to mean a straight-chain or branchedhydrocarbon chain, for example methyl, ethyl, isopropyl, tert-butyl,hexyl. The alkyl radicals may be mono- or polysubstituted as describedabove.

An aryl radical is understood to mean a phenyl, naphthyl, biphenyl,tetrahydronaphthyl, alpha- or beta-tetralonyl, indanyl or indan-1-onylradical. The aryl radicals may be mono- or polysubstituted by suitablegroups as described above.

“Heterocycle” and “heterocyclic radical” are understood to mean ringsand ring systems which, apart from carbon, also contain heteroatoms, forexample nitrogen, oxygen or sulfur. In addition, this definition alsoincludes ring systems in which the heterocycle or the heterocyclicradical is fused to a further ring system. The heterocycle or theheterocyclic radical may be saturated, partly saturated or aromatic.

Suitable “heterocycles” or “heterocyclic radicals” are acridinyl,azepanyl, azocinyl, benzimidazolyl, benzofuryl, benzothienyl,benzothiophenyl, benzoxazolyl, benzothiazolyl, benzotriazolyl,benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalinyl,carbazolyl, 4H-carbazolyl, carbolinyl, quinazolinyl, quinolinyl,4H-quinolizinyl, quinoxalinyl, quinuclidinyl, chromanyl, chromenyl,cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,dihydrofuro[2,3-b]-tetrahydrofuran,5,6-dihydro-4H-cyclopentathiazol-2-yl, 4,5-dihydrothiazol-2-yl, furyl,furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl,indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl,isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl(benzimidazolyl), isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl,octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl,oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl,phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl,piperazinyl, piperidinyl, pteridinyl, purinyl, pyranyl, pyrazinyl,pyroazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole,pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl,pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl,4,5,6,7-tetrahydrobenzooxazol-2-yl,4,5,6,7-tetrahydro-benzothiazol-2-yl,4,5,6,7-tetrahydrobenzoimidazol-2-yl,4,5,6,7-tetrahydro-pyrazolo[1,5-a]pyridin-2-yl, tetrahydrofuranyl,tetrahydropyranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl,6H-1,2,5-thiadazinyl, thiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thienyl, triazinyl, triazolyl,tetrazolyl, thiazolo[4,5-b]pyridinyl, thieno[2,3-d]thiazol-2-yl,tropanyl and xanthenyl.

The heterocycles or heterocyclic radicals may be mono- orpolysubstituted by suitable groups as described above.

The invention also encompasses solvates, hydrates and alcohol adducts ofthe compounds of the formula I.

The compound(s) of the formula I may also be administered in combinationwith further active ingredients.

The amount of a compound of the formula I necessary to achieve thedesired biological effect depends on a number of factors, for examplethe specific compound chosen, the intended use, the mode ofadministration and the clinical condition of the patient. The daily doseis generally in the range from 0.3 mg to 100 mg (typically from 3 mg to50 mg) per day and per kilogram of body weight, for example 3-10mg/kg/day. An intravenous dose may be, for example, in the range from0.3 mg to 1.0 mg/kg, which can suitably be administered as infusion of10 ng to 100 ng per kilogram and per minute. Suitable infusion solutionsfor these purposes may contain, for example, 0.1 ng to 100 mg, typically1 ng to 100 mg, per milliliter. Single doses may contain, for example, 1mg to 10 g of the active ingredient. Thus, ampoules for injections maycontain, for example, from 1 mg to 100 mg, and orally administrablesingle-dose formulations, for example tablets or capsules, may contain,for example, from 1.0 to 1000 mg, typically from 10 to 600 mg. Fortreatment of the abovementioned conditions, the compounds of the formulaI themselves may be used as the compound, but they are preferablypresent with a compatible carrier in the form of a pharmaceuticalcomposition. The carrier must, of course, be acceptable in the sensethat it is compatible with the other ingredients of the composition andis not harmful for the patient's health. The carrier may be a solid or aliquid or both and is preferably formulated with the compound as asingle dose, for example as a tablet, which may contain 0.05% to 95% byweight of the active ingredient. Other pharmaceutically activesubstances may likewise be present, including other compounds of formulaI. The pharmaceutical compositions of the invention can be produced byone of the known pharmaceutical methods, which essentially consist ofmixing the ingredients with pharmacologically acceptable carriers and/orexcipients.

Pharmaceutical compositions of the invention are those suitable fororal, rectal, topical, peroral (for example sublingual) and parenteral(for example subcutaneous, intramuscular, intradermal or intravenous)administration, although the most suitable mode of administrationdepends in each individual case on the nature and severity of thecondition to be treated and on the nature of the compound of formula Iused in each case. Coated formulations and coated slow-releaseformulations also belong within the framework of the invention.Preference is given to acid- and gastric juice-resistant formulations.Suitable coatings resistant to gastric juice comprise cellulose acetatephthalate, polyvinyl acetate phthalate, hydroxypropylmethylcellulosephthalate and anionic polymers of methacrylic acid and methylmethacrylate.

Suitable pharmaceutical compounds for oral administration may be in theform of separate units, for example capsules, cachets, lozenges ortablets, each of which contains a defined amount of the compound offormula I; as powders or granules; as solution or suspension in anaqueous or nonaqueous liquid; or as an oil-in-water or water-in-oilemulsion. These compositions may, as already mentioned, be prepared byany suitable pharmaceutical method which includes a step in which theactive ingredient and the carrier (which may consist of one or moreadditional ingredients) are brought into contact. The compositions aregenerally produced by uniform and homogeneous mixing of the activeingredient with a liquid and/or finely divided solid carrier, afterwhich the product is shaped if necessary. Thus, for example, a tabletcan be produced by compressing or molding a powder or granules of thecompound, where appropriate with one or more additional ingredients.Compressed tablets can be produced by tableting the compound infree-flowing form such as, for example, a powder or granules, whereappropriate mixed with a binder, glidant, inert diluent and/or one (ormore) surfactant(s)/dispersant(s) in a suitable machine. Molded tabletscan be produced by molding the compound, which is in powder form and hasbeen moistened with an inert liquid diluent, in a suitable machine.

Pharmaceutical compositions which are suitable for peroral (sublingual)administration comprise lozenges which contain a compound of formula Iwith a flavoring, typically sucrose, and gum arabic or tragacanth, andpastilles which comprise the compound in an inert base such as gelatinand glycerol or sucrose and gum arabic.

Pharmaceutical compositions suitable for parenteral administrationcomprise preferably sterile aqueous preparations of a compound offormula I, which are preferably isotonic with the blood of the intendedrecipient. These preparations are preferably administered intravenously,although administration may also take place by subcutaneous,intramuscular or intradermal injection. These preparations canpreferably be produced by mixing the compound with water and making theresulting solution sterile and isotonic with blood. Injectablecompositions of the invention generally contain 0.1 to 5% by weight ofthe active compound.

Pharmaceutical compositions suitable for rectal administration arepreferably in the form of single-dose suppositories. These can beproduced by mixing a compound of formula I with one or more conventionalsolid carriers, for example cocoa butter, and shaping resulting mixture.

Pharmaceutical compositions suitable for topical use on the skin arepreferably in the form of ointment, cream, lotion, paste, spray, aerosolor oil. The carriers used may be petrolatum, lanolin, polyethyleneglycols, alcohols and combinations of two or more of these substances.The active ingredient is generally present in a concentration of 0.1 to15% by weight of the composition, for example 0.5 to 2%.

Transdermal administration is also possible. Pharmaceutical compositionssuitable for transdermal uses may be in the form of single patches whichare suitable for long-term close contact with the patient's epidermis.Such patches suitably contain the active ingredient in an aqueoussolution which is buffered where appropriate, dissolved and/or dispersedin an adhesive or dispersed in a polymer. A suitable active ingredientconcentration is about 1% to 35%, preferably about 3% to 15%. Aparticular option is for the active ingredient to be released byelectrotransport or iontophoresis as described, for example, inPharmaceutical Research, 2(6): 318 (1986).

Further suitable active ingredients for the combination preparationsare:

All antidiabetics mentioned in the Rote Liste 2010, chapter 12; allweight-reducing agents/appetite suppressants mentioned in the Rote Liste2010, chapter 1; all diuretics mentioned in the Rote Liste 2010, chapter36; all lipid-lowering agents mentioned in the Rote Liste 2010, chapter58. They can be combined with the inventive compound of the formula I,especially for a synergistic improvement in action. The activeingredient combination can be administered either by separateadministration of the active ingredients to the patient or in the formof combination products in which a plurality of active ingredients arepresent in one pharmaceutical preparation. When the active ingredientsare administered by separate administration of the active ingredients,this can be done simultaneously or successively. Most of the activeingredients mentioned hereinafter are disclosed in the USP Dictionary ofUSAN and International Drug Names, US Pharmacopeia, Rockville 2006.

Antidiabetics include insulin and insulin derivatives, for exampleLantus® (see www.lantus.com) or HMR 1964 or Levemir® (insulin detemir),Humalog® (Insulin Lispro), insulin degludec, insulin aspart,polyethylene glycosidized (PEGylated) Insulin Lispro as described inWO2009152128, Humulin®, VIAject™, SuliXen®, VIAject™ or those asdescribed in WO2005005477 (Novo Nordisk), fast-acting insulins (see U.S.Pat. No. 6,221,633), inhalable insulins, for example Exubera®, Nasulin™or oral insulins, for example IN-105 (Nobex) or Oral-lyn™ (GenerexBiotechnology), or Technosphere® insulin (MannKind) or Cobalamin™ oralinsulin or ORMD-0801 or insulins or insulin precursors as described inWO2007128815, WO2007128817, WO2008034881, WO2008049711, WO2008145721,WO2009034117, WO2009060071, WO2009133099 or insulins which can beadministered transdermally; additionally included are also those insulinderivatives which are bonded to albumin by a bifunctional linker, asdescribed, for example, in WO2009121884;

GLP-1 derivatives and GLP-1 agonists, for example exenatide or specificformulations thereof, as described, for example, in WO2008061355,WO2009080024, WO2009080032, liraglutide, taspoglutide (R-1583),albiglutide, lixisenatide or those which have been disclosed in WO98/08871, WO2005027978, WO2006037811, WO2006037810 by Novo Nordisk A/S,in WO 01/04156 by Zealand or in WO 00/34331 by Beaufour-Ipsen,pramlintide acetate (Symlin; Amylin Pharmaceuticals), inhalable GLP-1(MKC-253 from MannKind) AVE-0010, BIM-51077 (R-1583, ITM-077),PC-DAC:exendin-4 (an exendin-4 analog which is bonded covalently torecombinant human albumin), biotinylated exendin (WO2009107900), aspecific formulation of exendin-4 as described in US2009238879, CVX-73,CVX-98 and CVx-96 (GLP-1 analogs which are bonded covalently to amonoclonal antibody which has specific binding sites for the GLP-1peptide), CNTO-736 (a GLP-1 analog which is bonded to a domain whichincludes the Fc portion of an antibody), PGC-GLP-1 (GLP-1 bonded to ananocarrier), agonists or modulators, as described, for example, in D.Chen et al., Proc. Natl. Acad. Sci. USA 104 (2007) 943, those asdescribed in WO2006124529, WO2007124461, WO2008062457, WO2008082274,WO2008101017, WO2008081418, WO2008112939, WO2008112941, WO2008113601,WO2008116294, WO2008116648, WO2008119238, WO2008148839, US2008299096,WO2008152403, WO2009030738, WO2009030771, WO2009030774, WO2009035540,WO2009058734, WO2009111700, WO2009125424, WO2009129696, WO2009149148,peptides, for example obinepitide (TM-30338), orally active GLP-1analogs (e.g. NN9924 from Novo Nordisk), amylin receptor agonists, asdescribed, for example, in WO2007104789, WO2009034119, analogs of thehuman GLP-1, as described in WO2007120899, WO2008022015, WO2008056726,chimeric pegylated peptides containing both GLP-1 and glucagon residues,as described, for example, in WO2008101017, WO2009155257, WO2009155258,glycosylated GLP-1 derivatives as described in WO2009153960, and orallyactive hypoglycemic ingredients.

Antidiabetics also include gastrin analogs, for example TT-223.

Antidiabetics additionally include poly- or monoclonal antibodiesdirected, for example, against interleukin 1 beta (IL-1β), for exampleXOMA-052.

Antidiabetics additionally include peptides which can bind to the humanpro-islet peptide (HIP) receptor, as described, for example, inWO2009049222.

Antidiabetics also include agonists of the glucose-dependentinsulinotropic polypeptide (GIP) receptor, as described, for example, inWO2006121860.

Antidiabetics also include the glucose-dependent insulinotropicpolypeptide (GIP), and also analogous compounds, as described, forexample, in WO2008021560, WO2010016935, WO2010016936, WO2010016938,WO2010016940, WO2010016944.

Additionally included are analogs and derivatives of human pancreaticpolypeptide, as described, for example, in WO2009007714.

Antidiabetics additionally include encapsulated insulin-producingporcine cells, for example DiabeCell®.

Antidiabetics also include analogs and derivatives of fibroblast growthfactor 21 (FGF-21), as described, for example, in WO2009149171,WO2010006214.

The orally active hypoglycemic ingredients preferably includesulfonylureas,

biguanidines,

meglitinides,

oxadiazolidinediones,

thiazolidinediones,

PPAR and RXR modulators,

glucosidase inhibitors,

inhibitors of glycogen phosphorylase,

glucagon receptor antagonists,

glucokinase activators,

inhibitors of fructose 1,6-bisphosphatase,

modulators of glucose transporter 4 (GLUT4),

inhibitors of glutamine:fructose-6-phosphate amidotransferase (GFAT),

GLP-1 agonists,

potassium channel openers, for example pinacidil, cromakalim, diazoxide,diazoxide choline salt, or those as described in R. D. Carr et al.,Diabetes 52, 2003, 2513.2518, in J. B. Hansen et al., Current MedicinalChemistry 11, 2004, 1595-1615, in T. M. Tagmose et al., J. Med. Chem.47, 2004, 3202-3211 or in M. J. Goghlan et al., J. Med. Chem. 44, 2001,1627-1653, or those which have been disclosed in WO 97/26265 and WO99/03861 by Novo Nordisk A/S,active ingredients which act on the ATP-dependent potassium channel ofthe beta cells,inhibitors of dipeptidyl peptidase-IV (DPP-IV),insulin sensitizers,inhibitors of liver enzymes involved in stimulating gluconeogenesisand/or glycogenolysis,modulators of glucose uptake, of glucose transport and of glucosereabsorption,modulators of sodium-dependent glucose transporter 1 or 2 (SGLT1,SGLT2),inhibitors of 11-beta-hydroxysteroid dehydrogenase-1 (11β-HSD1),inhibitors of protein tyrosine phosphatase-1B (PTP-1B),nicotinic acid receptor agonists,inhibitors of hormone-sensitive or endothelial lipases,inhibitors of acetyl-CoA carboxylase (ACC1 and/or ACC2) orinhibitors of GSK-3 beta.

Also included are compounds which modify the lipid metabolism, such asactive antihyperlipidemic ingredients and active antilipidemicingredients,

HMG-CoA reductase inhibitors,

farnesoid X receptor (FXR) modulators,

fibrates,

cholesterol absorption inhibitors,

CETP inhibitors,

bile acid absorption inhibitors,

MTP inhibitors,

agonists of estrogen receptor gamma (ERRγ agonists),

Sigma-1 receptor antagonists,

antagonists of the somatostatin 5 receptor (SST5 receptor);

compounds which reduce food intake, and

compounds which increase thermogenesis.

In one embodiment of the invention, the compound of the formula I isadministered in combination with insulin.

In another embodiment of the invention, the compound of the formula I isadministered in combination with an insulin sensitizer, for examplePN-2034 or ISIS-113715.

In one embodiment, the compound of the formula I is administered incombination with an active ingredient which acts on the ATP-dependentpotassium channel of the beta cells, for example sulfonylureas, forexample tolbutamide, glibenclamide, glipizide, gliclazide orglimepiride, or those formulations as described, for example, inEP2103302.

In one embodiment, the compound of the formula I is administered incombination with a tablet which comprises both glimepiride, which isreleased rapidly, and metformin, which is released over a longer period(as described, for example, in US2007264331, WO2008050987,WO2008062273).

In one embodiment, the compound of the formula I is administered incombination with a biguanide, for example metformin or one of its salts.

In a further embodiment, the compound of the formula I is administeredin combination with a guanidine, for example benzylguanidine or one ofits salts, or those guanidines as described in WO2009087395.

In another embodiment, the compound of the formula I is administered incombination with a meglitinide, for example repaglinide, nateglinide ormitiglinide.

In a further embodiment, the compound of the formula I is administeredwith a combination of mitiglinide with a glitazone, e.g. pioglitazonehydrochloride.

In a further embodiment, the compound of the formula I is administeredwith a combination of mitiglinide with an alpha-glucosidase inhibitor.

In a further embodiment, the compound of the formula I is administeredin combination with antidiabetic compounds, as described inWO2007095462, WO2007101060, WO2007105650.

In a further embodiment, the compound of the formula I is administeredin combination with antihypoglycemic compounds, as described inWO2007137008, WO2008020607.

In one embodiment, the compound of the formula I is administered incombination with a thiazolidinedione, for example troglitazone,ciglitazone, pioglitazone, rosiglitazone or the compounds disclosed inWO 97/41097 by Dr. Reddy's Research Foundation, especially5-[[4-[(3,4-dihydro-3-methyl-4-oxo-2-quinazolinylmethoxy]-phenyl]methyl]-2,4-thiazolidinedione.

In one embodiment of the invention, the compound of the formula I isadministered in combination with a PPAR gamma agonist, for examplerosiglitazone, pioglitazone, JTT-501, GI 262570, R-483, CS-011(rivoglitazone), DRL-17564, DRF-2593 (balaglitazone), INT-131, T-2384,or those as described in WO2005086904, WO2007060992, WO2007100027,WO2007103252, WO2007122970, WO2007138485, WO2008006319, WO2008006969,WO2008010238, WO2008017398, WO2008028188, WO2008066356, WO2008084303,WO2008089461-WO2008089464, WO2008093639, WO2008096769, WO2008096820,WO2008096829, US2008194617, WO2008099944, WO2008108602, WO2008109334,WO2008110062, WO2008126731, WO2008126732, WO2008137105, WO2009005672,WO2009038681, WO2009046606, WO2009080821, WO2009083526, WO2009102226,WO2009128558, WO2009139340.

In one embodiment of the invention, the compound of the formula I isadministered in combination with Competact™, a solid combination ofpioglitazone hydrochloride with metformin hydrochloride.

In one embodiment of the invention, the compound of the formula I isadministered in combination with Tandemact™, a solid combination ofpioglitazone with glimepiride.

In a further embodiment of the invention, the compound of the formula Iis administered in combination with a solid combination of pioglitazonehydrochloride with an angiotensin II agonist, for example TAK-536.

In one embodiment of the invention, the compound of the formula I isadministered in combination with a PPAR alpha agonist or mixed PPARalpha/PPAR delta agonist, for example GW9578, GW-590735, K-111, LY-674,KRP-101, DRF-10945, LY-518674, CP-900691, BMS-687453, BMS-711939, orthose as described in WO2001040207, WO2002096894, WO2005097076,WO2007056771, WO2007087448, WO2007089667, WO2007089557, WO2007102515,WO2007103252, JP2007246474, WO2007118963, WO2007118964, WO2007126043,WO2008006043, WO2008006044, WO2008012470, WO2008035359, WO2008087365,WO2008087366, WO2008087367, WO2008117982, JP2009023975, WO2009033561,WO2009047240, WO2009072581, WO2009080248, WO2009080242, WO2009149819,WO2009149820, WO2009147121, WO2009153496, WO2010008299, WO2010014771.

In one embodiment of the invention, the compound of the formula I isadministered in combination with a mixed PPAR alpha/gamma agonist, forexample naveglitazar, aleglitazar, LY-510929, ONO-5129, E-3030, AVE8042, AVE 8134, AVE 0847, CKD-501 (lobeglitazone sulfate), MBX-213,KY-201, BMS-759509, or as described in WO 00/64888, WO 00/64876,WO03/020269, WO2004024726, WO2007099553, US2007276041, WO2007085135,WO2007085136, WO2007141423, WO2008016175, WO2008053331, WO2008109697,WO2008109700, WO2008108735, WO2009026657, WO2009026658, WO2009149819,WO2009149820 or in J. P. Berger et al., TRENDS in PharmacologicalSciences 28(5), 244-251, 2005.

In one embodiment of the invention, the compound of the formula I isadministered in combination with a PPAR delta agonist, for exampleGW-501516, or as described in WO2006059744, WO2006084176, WO2006029699,WO2007039172-WO2007039178, WO2007071766, WO2007101864, US2007244094,WO2007119887, WO2007141423, US2008004281, WO2008016175, WO2008066356,WO2008071311, WO2008084962, US2008176861, WO2009012650, US2009137671,WO2009080223, WO2009149819, WO2009149820, WO2010000353.

In one embodiment of the invention, the compound of the formula I isadministered in combination with a pan-SPPARM (selective PPAR modulatoralpha, gamma, delta), for example GFT-505, indeglitazar, or those asdescribed in WO2008035359, WO2009072581.

In one embodiment, the compound of the formula I is administered incombination with metaglidasen or with MBX-2044 or other partial PPARgamma agonists/antagonists.

In one embodiment, the compound of the formula I is administered incombination with an α-glucosidase inhibitor, for example miglitol oracarbose, or those as described, for example, in WO2007114532,WO2007140230, US2007287674, US2008103201, WO2008065796, WO2008082017,US2009076129.

In one embodiment, the compound of the formula I is administered incombination with an inhibitor of glycogen phosphorylase, for examplePSN-357 or FR-258900, or those as described in WO2003084922,WO2004007455, WO2005073229-31, WO2005067932, WO2008062739, WO2008099000,WO2008113760, WO2009016118, WO2009016119, WO2009030715, WO2009045830,WO2009045831, WO2009127723.

In another embodiment, the compound of the formula I is administered incombination with an inhibitor of the interaction of liver glycogenphosphorylase with the protein PPP1R3 (GL subunit of glycogen-associatedprotein phosphatase 1 (PP1)), as described, for example, inWO2009030715.

In one embodiment, the compound of the formula I is administered incombination with glucagon receptor antagonists, for example A-770077 orNNC-25-2504 or as described in WO2004100875, WO2005065680, WO2006086488,WO2007047177, WO2007106181, WO2007111864, WO2007120270, WO2007120284,WO2007123581, WO2007136577, WO2008042223, WO2008098244, WO2009057784,WO2009058662, WO2009058734, WO2009110520, WO2009120530, WO2009140342,WO2010019828.

In a further embodiment, the compound of the formula I is administeredin combination with an antisense compound, e.g. ISIS-325568, whichinhibits the production of the glucagon receptor.

In one embodiment, the compound of the formula I is administered incombination with activators of glucokinase, for example LY-2121260(WO2004063179), PSN-105, PSN-110, GKA-50, or those as described, forexample, in WO2004072031, WO2004072066, WO2005080360, WO2005044801,WO2006016194, WO2006058923, WO2006112549, WO2006125972, WO2007017549,WO2007017649, WO2007007910, WO2007007040-42, WO2007006760-61,WO2007006814, WO2007007886, WO2007028135, WO2007031739, WO2007041365,WO2007041366, WO2007037534, WO2007043638, WO2007053345, WO2007051846,WO2007051845, WO2007053765, WO2007051847, WO2007061923, WO2007075847,WO2007089512, WO2007104034, WO2007117381, WO2007122482, WO2007125103,WO2007125105, US2007281942, WO2008005914, WO2008005964, WO2008043701,WO2008044777, WO2008047821, US2008096877, WO2008050117, WO2008050101,WO2008059625, US2008146625, WO2008078674, WO2008079787, WO2008084043,WO2008084044, WO2008084872, WO2008089892, WO2008091770, WO2008075073,WO2008084043, WO2008084044, WO2008084872, WO2008084873, WO2008089892,WO2008091770, JP2008189659, WO2008104994, WO2008111473, WO2008116107,WO2008118718, WO2008120754, US2008280875, WO2008136428, WO2008136444,WO2008149382, WO2008154563, WO2008156174, WO2008156757, US2009030046,WO2009018065, WO2009023718, WO2009039944, WO2009042435, WO2009046784,WO2009046802, WO2009047798, WO2009063821, WO2009081782, WO2009082152,WO2009083553, WO2009091014, US2009181981, WO2009092432, WO2009099080,WO2009106203, WO2009106209, WO2009109270, WO2009125873, WO2009127544,WO2009127546, WO2009128481, WO2009133687, WO2009140624, WO2010013161,WO2010015849, WO2010018800.

In one embodiment, the compound of the formula I is administered incombination with an inhibitor of gluconeogenesis, as described, forexample, in FR-225654, WO2008053446.

In one embodiment, the compound of the formula I is administered incombination with inhibitors of fructose 1,6-bisphosphatase (FBPase), forexample MB-07729, CS-917 (MB-06322) or MB-07803, or those as describedin WO2006023515, WO2006104030, WO2007014619, WO2007137962, WO2008019309,WO2008037628, WO2009012039, EP2058308, WO2009068467, WO2009068468.

In one embodiment, the compound of the formula I is administered incombination with modulators of glucose transporter 4 (GLUT4), forexample KST-48 (D.-O. Lee et al.: Arzneim.-Forsch. Drug Res. 54 (12),835 (2004)).

In one embodiment, the compound of the formula I is administered incombination with inhibitors of glutamine:fructose-6-phosphateamidotransferase (GFAT), as described, for example, in WO2004101528.

In one embodiment, the compound of the formula I is administered incombination with inhibitors of dipeptidyl peptidase-IV (DPP-IV), forexample vildagliptin (LAF-237), sitagliptin (MK-0431), sitagliptinphosphate, saxagliptin (BMS-477118), GSK-823093, PSN-9301, SYR-322,SYR-619, TA-6666, TS-021, GRC-8200 (melogliptin), GW-825964X, KRP-104,DP-893, ABT-341, ABT-279 or another salt thereof, S-40010, S-40755,PF-00734200, BI-1356, PHX-1149, DSP-7238, alogliptin benzoate,linagliptin, melogliptin, carmegliptin, or those compounds as describedin WO2003074500, WO2003106456, WO2004037169, WO200450658, WO2005037828,WO2005058901, WO2005012312, WO2005/012308, WO2006039325, WO2006058064,WO2006015691, WO2006015701, WO2006015699, WO2006015700, WO2006018117,WO2006099943, WO2006099941, JP2006160733, WO2006071752, WO2006065826,WO2006078676, WO2006073167, WO2006068163, WO2006085685, WO2006090915,WO2006104356, WO2006127530, WO2006111261, US2006890898, US2006803357,US2006303661, WO2007015767 (LY-2463665), WO2007024993, WO2007029086,WO2007063928, WO2007070434, WO2007071738, WO2007071576, WO2007077508,WO2007087231, WO2007097931, WO2007099385, WO2007100374, WO2007112347,WO2007112669, WO2007113226, WO2007113634, WO2007115821, WO2007116092,US2007259900, EP1852108, US2007270492, WO2007126745, WO2007136603,WO2007142253, WO2007148185, WO2008017670, US2008051452, WO2008027273,WO2008028662, WO2008029217, JP2008031064, JP2008063256, WO2008033851,WO2008040974, WO2008040995, WO2008060488, WO2008064107, WO2008066070,WO2008077597, JP2008156318, WO2008087560, WO2008089636, WO2008093960,WO2008096841, WO2008101953, WO2008118848, WO2008119005, WO2008119208,WO2008120813, WO2008121506, WO2008130151, WO2008131149, WO2009003681,WO2009014676, WO2009025784, WO2009027276, WO2009037719, WO2009068531,WO2009070314, WO2009065298, WO2009082134, WO2009082881, WO2009084497,WO2009093269, WO2009099171, WO2009099172, WO2009111239, WO2009113423,WO2009116067, US2009247532, WO2010000469, WO2010015664.

In one embodiment, the compound of the formula I is administered incombination with Janumet™, a solid combination of sitagliptin phosphatewith metformin hydrochloride.

In one embodiment, the compound of the formula I is administered incombination with Eucreas®, a solid combination of vildagliptin withmetformin hydrochloride.

In a further embodiment, the compound of the formula I is administeredin combination with a solid combination of alogliptin benzoate withpioglitazone.

In one embodiment, the compound of the formula I is administered incombination with a solid combination of a salt of sitagliptin withmetformin hydrochloride.

In one embodiment, the compound of the formula I is administered incombination with a combination of a DPP-IV inhibitor with omega-3 fattyacids or omega-3 fatty acid esters, as described, for example, inWO2007128801.

In one embodiment, the compound of the formula I is administered incombination with a combination of a DPP-IV inhibitor with metforminhydrochloride, as described, for example, in WO2009121945.

In one embodiment, the compound of the formula I is administered incombination with a combination of a DPP-IV inhibitor with a GPR-119agonist, as described, for example, in WO2009123992.

In one embodiment, the compound of the formula I is administered incombination with a combination of a DPP-1V inhibitor with miglitol, asdescribed, for example, in WO2009139362.

In one embodiment, the compound of the formula I is administered incombination with a solid combination of a salt of sitagliptin withmetformin hydrochloride.

In one embodiment, the compound of the formula I is administered incombination with a solid combination of alopliptin benzoate withpioglitazone hydrochloride.

In one embodiment, the compound of the formula I is administered incombination with a substance which enhances insulin secretion, forexample KCP-265 (WO2003097064), or those as described in WO2007026761,WO2008045484, US2008194617, WO2009109259, WO2009109341.

In one embodiment, the compound of the formula I is administered incombination with agonists of the glucose-dependent insulinotropicreceptor (GDIR), for example APD-668.

In one embodiment of the invention, the compound of the formula I isadministered in combination with an ATP citrate lyase inhibitor, forexample SB-204990.

In one embodiment, the compound of the formula I is administered incombination with modulators of the sodium-dependent glucose transporter1 and/or 2 (SGLT1, SGLT2), for example KGA-2727, T-1095, SGL-0010, AVE2268, SAR 7226, SGL-5083, SGL-5085, SGL-5094, ISIS-388626, sergliflozin,dapagliflozin or remogliflozin etabonate, canagliflozin, or asdescribed, for example, in WO2004007517, WO200452903, WO200452902,PCT/EP2005/005959, WO2005085237, JP2004359630, WO2005121161,WO2006018150, WO2006035796, WO2006062224, WO2006058597, WO2006073197,WO2006080577, WO2006087997, WO2006108842, WO2007000445, WO2007014895,WO2007080170, WO2007093610, WO2007126117, WO2007128480, WO2007129668,US2007275907, WO2007136116, WO2007143316, WO2007147478, WO2008001864,WO2008002824, WO2008013277, WO2008013280, WO2008013321, WO2008013322,WO2008016132, WO2008020011, JP2008031161, WO2008034859, WO2008042688,WO2008044762, WO2008046497, WO2008049923, WO2008055870, WO2008055940,WO2008069327, WO2008070609, WO2008071288, WO2008072726, WO2008083200,WO2008090209, WO2008090210, WO2008101586, WO2008101939, WO2008116179,WO2008116195, US2008242596, US2008287529, WO2009026537, WO2009049731,WO2009076550, WO2009084531, WO2009096503, WO2009100936, WO2009121939,WO2009124638, WO2009128421, WO2009135673, WO2010009197, WO2010018435,WO2010018438 or by A. L. Handlon in Expert Opin. Ther. Patents (2005)15(11), 1531-1540.

In a further embodiment of the invention, the compound of the formula Iis administered in combination with a solid combination of an SGLTinhibitor with a DPP-IV inhibitor, as described in WO2009091082.

In one embodiment, the compound of the formula I is administered incombination with a stimulator of glucose transport, as described, forexample, in WO2008136392, WO2008136393.

In one embodiment, the compound of the formula I is administered incombination with inhibitors of 11-beta-hydroxysteroid dehydrogenase 1(11β-HSD1), for example BVT-2733, JNJ-25918646, INCB-13739, INCB-20817,DIO-92 ((−)-ketoconazole) or those as described, for example, inWO200190090-94, WO200343999, WO2004112782, WO200344000, WO200344009,WO2004112779, WO2004113310, WO2004103980, WO2004112784, WO2003065983,WO2003104207, WO2003104208, WO2004106294, WO2004011410, WO2004033427,WO2004041264, WO2004037251, WO2004056744, WO2004058730, WO2004065351,WO2004089367, WO2004089380, WO2004089470-71, WO2004089896, WO2005016877,WO2005063247, WO2005097759, WO2006010546, WO2006012227, WO2006012173,WO2006017542, WO2006034804, WO2006040329, WO2006051662, WO2006048750,WO2006049952, WO2006048331, WO2006050908, WO2006024627, WO2006040329,WO2006066109, WO2006074244, WO2006078006, WO2006106423, WO2006132436,WO2006134481, WO2006134467, WO2006135795, WO2006136502, WO2006138508,WO2006138695, WO2006133926, WO2007003521, WO2007007688, US2007066584,WO2007029021, WO2007047625, WO2007051811, WO2007051810, WO2007057768,WO2007058346, WO2007061661, WO2007068330, WO2007070506, WO2007087150,WO2007092435, WO2007089683, WO2007101270, WO2007105753, WO2007107470,WO2007107550, WO2007111921, US2007207985, US2007208001, WO2007115935,WO2007118185, WO2007122411, WO2007124329, WO2007124337, WO2007124254,WO2007127688, WO2007127693, WO2007127704, WO2007127726, WO2007127763,WO2007127765, WO2007127901, US2007270424, JP2007291075, WO2007130898,WO2007135427, WO2007139992, WO2007144394, WO2007145834. WO2007145835,WO2007146761, WO2008000950, WO2008000951, WO2008003611, WO2008005910,WO2008006702, WO2008006703, WO2008011453, WO2008012532, WO2008024497,WO2008024892, WO2008032164, WO2008034032, WO2008043544, WO2008044656,WO2008046758, WO2008052638, WO2008053194, WO2008071169, WO2008074384,WO2008076336, WO2008076862, WO2008078725, WO2008087654, WO2008088540,WO2008099145, WO2008101885, WO2008101886, WO2008101907, WO2008101914,WO2008106128, WO2008110196, WO2008119017, WO2008120655, WO2008127924,WO2008130951, WO2008134221, WO2008142859, WO2008142986, WO2008157752,WO2009001817, WO2009010416, WO2009017664, WO2009020140, WO2009023180,WO2009023181, WO2009023664, WO2009026422, WO2009038064, WO2009045753,WO2009056881, WO2009059666, WO2009061498, WO2009063061, WO2009070497,WO2009074789, WO2009075835, WO2009088997, WO2009090239, WO2009094169,WO2009098501, WO2009100872, WO2009102428, WO2009102460, WO2009102761,WO2009106817, WO2009108332, WO2009112691, WO2009112845, WO2009114173,WO2009117109, US2009264401, WO2009118473, WO2009131669, WO2009132986,WO2009134384, WO2009134387, WO2009134392, WO2009134400, WO2009135581,WO2009138386, WO2010006940, WO2010010157, WO2010010174, WO2010011917.

In one embodiment, the compound of the formula I is administered incombination with inhibitors of protein tyrosine phosphatase-1B (PTP-1B),as described, for example, in WO200119830-31, WO200117516, WO2004506446,WO2005012295, WO2005116003, WO2005116003, WO2006007959, DE 10 2004060542.4, WO2007009911, WO2007028145, WO2007067612-615, WO2007081755,WO2007115058, US2008004325, WO2008033455, WO2008033931, WO2008033932,WO2008033934, WO2008089581, WO2008148744, WO2009032321, WO2009109999,WO2009109998.

In a further embodiment, the compound of the formula I is administeredin combination with stimulators of tyrosine kinase B (Trk-B), asdescribed, for example, in WO2010014613.

In one embodiment of the invention, the compound of the formula I isadministered in combination with an agonist of GPR109A (HM74A receptoragonists; NAR agonists (nicotinic acid receptor agonists)), for examplenicotinic acid or extended release niacin in conjunction with MK-0524A(laropiprant) or MK-0524, or those compounds as described inWO2004041274, WO2006045565, WO2006045564, WO2006069242, WO2006085108,WO2006085112, WO2006085113 WO2006124490, WO2006113150, WO2007002557,WO2007017261, WO2007017262, WO2007017265, WO2007015744, WO2007027532,WO2007092364, WO2007120575, WO2007134986, WO2007150025, WO2007150026,WO2008016968, WO2008051403, WO2008086949, WO2008091338, WO2008097535,WO2008099448, US2008234277, WO2008127591.

In another embodiment of the invention, the compound of the formula I isadministered in combination with a solid combination of niacin withsimvastatin.

In another embodiment of the invention, the compound of the formula I isadministered in combination with nicotinic acid or “extended releaseniacin” in conjunction with MK-0524A (laropiprant).

In a further embodiment of the invention, the compound of the formula Iis administered in combination with nicotinic acid or “extended releaseniacin” in conjunction with MK-0524A (laropiprant) and with simvastatin.

In one embodiment of the invention, the compound of the formula I isadministered in combination with nicotinic acid or another nicotinicacid receptor agonist and a prostaglandin DP receptor antagonist, forexample those as described in WO2008039882.

In another embodiment of the invention, the compound of the formula I isadministered in combination with a solid combination of niacin withmeloxicam, as described, for example, in WO2009149056.

In another embodiment of the invention, the compound of the formula I isadministered in combination with an agonist of GPR116, as described, forexample, in WO2006067531, WO2006067532.

In one embodiment, the compound of the formula I is administered incombination with modulators of GPR40, as described, for example, inWO2007013689, WO2007033002, WO2007106469, US2007265332, WO2007123225,WO2007131619, WO2007131620, WO2007131621, US2007265332, WO2007131622,WO2007136572, WO2008001931, WO2008030520, WO2008030618, WO2008054674,WO2008054675, WO2008066097, US2008176912, WO2008130514, WO2009038204,WO2009039942, WO2009039943, WO2009048527, WO2009054479, WO2009058237,WO2009111056, WO2010012650.

In one embodiment, the compound of the formula I is administered incombination with modulators of GPR119 (G-protein-coupledglucose-dependent insulinotropic receptor), for example PSN-119-1,PSN-821, PSN-119-2, MBX-2982 or those as described, for example, inWO2004065380, WO2005061489 (PSN-632408), WO2006083491, WO2007003960-62and WO2007003964, WO2007035355, WO2007116229, WO2007116230,WO2008005569, WO2008005576, WO2008008887, WO2008008895, WO2008025798,WO2008025799, WO2008025800, WO2008070692, WO2008076243, WO200807692,WO2008081204, WO2008081205, WO2008081206, WO2008081207, WO2008081208,WO2008083238, WO2008085316, WO2008109702, WO2008130581, WO2008130584,WO2008130615, WO2008137435, WO2008137436, WO2009012275, WO2009012277,WO2009014910, WO2009034388, WO2009038974, WO2009050522, WO2009050523,WO2009055331, WO2009105715, WO2009105717, WO2009105722, WO2009106561,WO2009106565, WO2009117421, WO2009125434, WO2009126535, WO2009129036,US2009286812, WO2009143049, WO2009150144, WO2010001166, WO2010004343,WO2010004344, WO2010004345, WO2010004346, WO2010004347, WO2010004348,WO2010008739, WO2010006191, WO2010009183, WO2010009195, WO2010009207,WO2010009208, WO2010014593.

In a further embodiment, the compound of the formula I is administeredin combination with modulators of GPR120, as described, for example, inEP1688138, WO2008066131, WO2008066131, WO2008103500, WO2008103501,WO2008139879, WO2009038204, WO2009147990, WO2010008831.

In another embodiment, the compound of the formula I is administered incombination with antagonists of GPR105, as described, for example, inWO2009000087, WO2009070873.

In a further embodiment, the compound of the formula I is administeredin combination with agonists of GPR43, for example ESN-282.

In one embodiment, the compound of the formula I is administered incombination with inhibitors of hormone-sensitive lipase (HSL) and/orphospholipases, as described, for example, in WO2005073199,WO2006074957, WO2006087309, WO2006111321, WO2007042178, WO2007119837,WO2008122352, WO2008122357, WO2009009287.

In one embodiment, the compound of the formula I is administered incombination with inhibitors of endothelial lipase, as described, forexample, in WO2007110216.

In one embodiment, the compound of the formula I is administered incombination with a phospholipase A2 inhibitor, for example darapladib orA-002, or those as described in WO2008048866, WO20080488867,US2009062369.

In one embodiment, the compound of the formula I is administered incombination with myricitrin, a lipase inhibitor (WO2007119827).

In one embodiment, the compound of the formula I is administered incombination with an inhibitor of glycogen synthase kinase-3 beta (GSK-3beta), as described, for example, in US2005222220, WO2005085230,WO2005111018, WO2003078403, WO2004022544, WO2003106410, WO2005058908,US2005038023, WO2005009997, US2005026984, WO2005000836, WO2004106343,EP1460075, WO2004014910, WO2003076442, WO2005087727, WO2004046117,WO2007073117, WO2007083978, WO2007120102, WO2007122634, WO2007125109,WO2007125110, US2007281949, WO2008002244, WO2008002245, WO2008016123,WO2008023239, WO2008044700, WO2008056266, WO2008057940, WO2008077138,EP1939191, EP1939192, WO2008078196, WO2008094992, WO2008112642,WO2008112651, WO2008113469, WO2008121063, WO2008121064, EP-1992620,EP-1992621, EP1992624, EP-1992625, WO2008130312, WO2009007029,EP2020232, WO2009017452, WO2009035634, WO2009035684, WO2009038385,WO2009095787, WO02009095788, WO2009095789, WO2009095792, WO2009145814,US2009291982, WO2009154697, WO2009156857, WO2009156859, WO2009156860,WO2009156861, WO2009156863, WO2009156864, WO2009156865, WO2010013168,WO2010014794.

In one embodiment, the compound of the formula I is administered incombination with an inhibitor of phosphoenolpyruvate carboxykinase(PEPCK), for example those as described in WO2004074288.

In one embodiment, the compound of the formula I is administered incombination with an inhibitor of phosphoinositide kinase-3 (PI3K), forexample those as described in WO2008027584, WO2008070150, WO2008125833,WO2008125835, WO2008125839, WO2009010530, WO2009026345, WO2009071888,WO2009071890, WO2009071895.

In one embodiment, the compound of the formula I is administered incombination with an inhibitor of serum/glucocorticoid-regulated kinase(SGK), as described, for example, in WO2006072354, WO2007093264,WO2008009335, WO2008086854, WO2008138448.

In one embodiment, the compound of the formula I is administered incombination with a modulator of the glucocorticoid receptor, asdescribed, for example, in WO2008057855, WO2008057856, WO2008057857,WO2008057859, WO2008057862, WO2008059867, WO2008059866, WO2008059865,WO2008070507, WO2008124665, WO2008124745, WO2008146871, WO2009015067,WO2009040288, WO2009069736, WO2009149139.

In one embodiment, the compound of the formula I is administered incombination with a modulator of the mineralocorticoid receptor (MR), forexample drospirenone, or those as described in WO2008104306,WO2008119918.

In one embodiment, the compound of the formula I is administered incombination with an inhibitor of protein kinase C beta (PKC beta), forexample ruboxistaurin, or those as described in WO2008096260,WO2008125945.

In one embodiment, the compound of the formula I is administered incombination with an inhibitor of protein kinase D, for example doxazosin(WO2008088006).

In a further embodiment, the compound of the formula I is administeredin combination with an activator/modulator of the AMP-activated proteinkinase (AMPK), as described, for example, in WO2007062568, WO2008006432,WO2008016278, WO2008016730, WO2008020607, WO2008083124, WO2008136642,WO2009019445, WO2009019446, WO2009019600, WO2009028891, WO2009065131,WO2009076631, WO2009079921, WO2009100130, WO2009124636, WO2009135580,WO2009152909.

In one embodiment, the compound of the formula I is administered incombination with an inhibitor of ceramide kinase, as described, forexample, in WO2007112914, WO2007149865.

In a further embodiment, the compound of the formula I is administeredin combination with an inhibitor of MAPK-interacting kinase 1 or 2 (MNK1or 2), as described, for example, in WO2007104053, WO2007115822,WO2008008547, WO2008075741.

In one embodiment, the compound of the formula I is administered incombination with inhibitors of “1-kappaB kinase” (IKK inhibitors), asdescribed, for example, in WO2001000610, WO2001030774, WO2004022057,WO2004022553, WO2005097129, WO2005113544, US2007244140, WO2008099072,WO2008099073, WO2008099073, WO2008099074, WO2008099075, WO2009056693,WO2009075277, WO2009089042, WO2009120801.

In another embodiment, the compound of the formula I is administered incombination with inhibitors of NF-kappaB (NFKB) activation, for examplesalsalate.

In a further embodiment, the compound of the formula I is administeredin combination with inhibitors of ASK-1 (apoptosis signal-regulatingkinase 1), as described, for example, in WO2008016131, WO2009123986.

In one embodiment of the invention, the compound of the formula I isadministered in combination with an HMG-CoA reductase inhibitor such assimvastatin, fluvastatin, pravastatin, lovastatin, atorvastatin,cerivastatin, rosuvastatin, pitavastatin, L-659699, BMS-644950,NCX-6560, or those as described in US2007249583, WO2008083551,WO2009054682.

In a further embodiment of the invention, the compound of the formula Iis administered in combination with a farnesoid X receptor (FXR)modulator, for example WAY-362450 or those as described in WO2003099821,WO2005056554, WO2007052843, WO2007070796, WO2007092751, JP2007230909,WO2007095174, WO2007140174, WO2007140183, WO2008000643, WO2008002573,WO2008025539, WO2008025540, JP2008214222, JP2008273847, WO2008157270,US2008299118, US2008300235, WO2009005998, WO2009012125, WO2009027264,WO2009062874, US2009131409, US2009137554, US2009163552, WO2009127321,EP2128158.

In another embodiment of the invention, the compound of the formula I isadministered in combination with a ligand of the liver X receptor (LXR),as described, for example, in WO2007092965, WO2008041003, WO2008049047,WO2008065754, WO2008073825, US2008242677, WO2009020683, US2009030082,WO2009021868, US2009069373, WO2009024550, WO2009040289, WO2009086123,WO2009086129, WO2009086130, WO2009086138, WO2009107387, US2009247587,WO2009133692, WO2008138438, WO2009144961. WO2009150109.

In one embodiment of the invention, the compound of the formula I isadministered in combination with a fibrate, for example fenofibrate,clofibrate, bezafibrate, or those as described in WO2008093655.

In one embodiment of the invention, the compound of the formula I isadministered in combination with fibrates, for example the choline saltof fenofibrate (SLV-348; Trilipix™).

In one embodiment of the invention, the compound of the formula I isadministered in combination with fibrates, for example the choline saltof fenofibrate (Trilipix™) and an HMG-CoA reductase inhibitor, forexample rosuvastatin.

In a further embodiment of the invention, the compound of the formula Iis administered in combination with bezafibrate and diflunisal.

In a further embodiment of the invention, the compound of the formula Iis administered in combination with a solid combination of fenofibrateor a salt thereof with simvastatin, rosuvastatin, fluvastatin,lovastatin, cerivastatin, pravastatin, pitavastatin or atorvastatin.

In a further embodiment of the invention, the compound of the formula Iis administered in combination with Synordia®, a solid combination offenofibrate with metformin.

In another embodiment of the invention, the compound of the formula I isadministered in combination with a solid combination of metformin withan MTP inhibitor, as described in WO2009090210.

In one embodiment of the invention, the compound of the formula I isadministered in combination with a cholesterol reabsorption inhibitor,for example ezetimibe, tiqueside, pamaqueside, FM-VP4(sitostanol/campesterol ascorbyl phosphate; Forbes Medi-Tech,WO2005042692, WO2005005453), MD-0727 (Microbia Inc., WO2005021497,WO2005021495) or with compounds as described in WO2002066464,WO2005000353 (Kotobuki Pharmaceutical Co. Ltd.) or WO2005044256 orWO2005062824 (Merck & Co.) or WO2005061451 and WO2005061452 (AstraZenecaAB) and WO2006017257 (Phenomix) or WO2005033100 (Lipideon BiotechnologyAG), or as described in WO2002050060, WO2002050068, WO2004000803,WO2004000804, WO2004000805, WO2004087655, WO2004097655, WO2005047248,WO2006086562, WO2006102674, WO2006116499, WO2006121861, WO2006122186,WO2006122216, WO2006127893, WO2006137794, WO2006137796, WO2006137782,WO2006137793, WO2006137797, WO2006137795, WO2006137792, WO2006138163,WO2007059871, US2007232688, WO2007126358, WO2008033431, WO2008033465,WO2008052658, WO2008057336, WO2008085300, WO2008104875, US2008280836,WO2008108486.

In one embodiment of the invention, the compound of the formula I isadministered in combination with an NPC1 L1 antagonist, for examplethose as described in WO2008033464, WO2008033465.

In one embodiment of the invention, the compound of the formula I isadministered in combination with Vytorin™, a solid combination ofezetimibe with simvastatin.

In one embodiment of the invention, the compound of the formula I isadministered in combination with a solid combination of ezetimibe withatorvastatin.

In one embodiment of the invention, the compound of the formula I isadministered in combination with a solid combination of ezetimibe withfenofibrate.

In one embodiment of the invention, the further active ingredient is adiphenylazetidinone derivative, as described, for example, in U.S. Pat.No. 6,992,067 or U.S. Pat. No. 7,205,290.

In a further embodiment of the invention, the further active ingredientis a diphenylazetidinone derivative, as described, for example, in U.S.Pat. No. 6,992,067 or U.S. Pat. No. 7,205,290, combined with a statin,for example simvastatin, fluvastatin, pravastatin, lovastatin,cerivastatin, atorvastatin, pitavastatin or rosuvastatin.

In one embodiment of the invention, the compound of the formula I isadministered in combination with a solid combination of lapaquistat, asqualene synthase inhibitor, with atorvastatin.

In a further embodiment of the invention, the compound of the formula Iis administered in combination with a conjugate consisting of theHMG-CoA reductase inhibitor atorvastatin with the renin inhibitoraliskiren (WO2009090158).

In one embodiment of the invention, the compound of the formula I isadministered in combination with a CETP inhibitor, for exampletorcetrapib, anacetrapib or JTT-705 (dalcetrapib), or those as describedin WO2006002342, WO2006010422, WO2006012093, WO2006073973, WO2006072362,WO2007088996, WO2007088999, US2007185058, US2007185113, US2007185154,US2007185182, WO2006097169, WO2007041494, WO2007090752, WO2007107243,WO2007120621, US2007265252, US2007265304, WO2007128568, WO2007132906,WO2008006257, WO2008009435, WO2008018529, WO2008058961, WO2008058967,WO2008059513, WO2008070496, WO2008115442, WO2008111604, WO2008129951,WO2008141077, US2009118287, WO2009062371, WO2009071509.

In one embodiment of the invention, the compound of the formula I isadministered in combination with bile acid reabsorption inhibitors(inhibitors of the intestinal bile acid transporter (IBAT)) (see, forexample, U.S. Pat. No. 6,245,744, U.S. Pat. No. 6,221,897 orWO00/61568), for example HMR 1741, or those as described in DE 10 2005033099.1 and DE 10 2005 033100.9, DE 10 2006 053635, DE 10 2006 053637,WO2007009655-56, WO2008058628, WO2008058629, WO2008058630, WO2008058631.

In one embodiment, the compound of the formula I is administered incombination with agonists of GPBAR1 (G-protein-coupled bile acidreceptor 1; TGR5), for example INT-777 or those as described, forexample, in US20060199795, WO2007110237, WO2007127505, WO2008009407,WO2008067219, WO2008067222, FR2908310, WO2008091540, WO2008097976,US2009054304, WO2009026241, WO2009146772, WO2010014739, WO2010014836.

In one embodiment, the compound of the formula I is administered incombination with modulators of histone deacetylase, for exampleursodeoxycholic acid, as described in WO2009011420.

In one embodiment, the compound of the formula I is administered incombination with inhibitors/modulators of the TRPM5 channel (TRP cationchannel M5), as described, for example, in WO2008097504, WO2009038722.

In one embodiment, the compound of the formula I is administered incombination with inhibitors/modulators of the TRPA1 channel (TRP cationchannel A1), as described, for example, in US2009176883, WO2009089083,WO2009144548.

In one embodiment, the compound of the formula I is administered incombination with inhibitors/modulators of the TRPV3 channel (TRP cationchannel V3), as described, for example, in WO2009084034, WO20091305611

In one embodiment of the invention, the compound of the formula I isadministered in combination with a polymeric bile acid adsorber, forexample cholestyramine, colesevelam hydrochloride.

In one embodiment of the invention, the compound of the formula I isadministered in combination with colesevelam hydrochloride and metforminor a sulfonylurea or insulin.

In one embodiment of the invention, the compound of the formula I isadministered in combination with tocotrienol and insulin or an insulinderivative.

In one embodiment of the invention, the compound of the formula I isadministered in combination with a chewing gum comprising phytosterols(Reductol™).

In one embodiment of the invention, the compound of the formula I isadministered in combination with an inhibitor of the microsomaltriglyceride transfer protein (MTP inhibitor), for example implitapide,BMS-201038, R-103757, AS-1552133, SLx-4090, AEGR-733, JTT-130, or thoseas described in WO2005085226, WO2005121091, WO2006010423, WO2006113910,WO2007143164, WO2008049806, WO2008049808, WO2008090198, WO2008100423,WO2009014674.

In a further embodiment of the invention, the compound of the formula Iis administered in combination with a combination of a cholesterolabsorption inhibitor, for example ezetimibe, and an inhibitor of thetriglyceride transfer protein (MTP inhibitor), for example implitapide,as described in WO2008030382 or in WO2008079398.

In one embodiment of the invention, the compound of the formula I isadministered in combination with an active antihypertriglyceridemicingredient, for example those as described in WO2008032980.

In another embodiment of the invention, the compound of the formula I isadministered in combination with an antagonist of the somatostatin 5receptor (SST5 receptor), for example those as described inWO2006094682.

In one embodiment of the invention, the compound of the formula I isadministered in combination with an ACAT inhibitor, for exampleavasimibe, SMP-797 or KY-382, or those as described in WO2008087029,WO2008087030, WO2008095189, WO2009030746, WO2009030747, WO2009030750,WO2009030752, WO2009070130, WO2009081957, WO2009081957.

In a further embodiment of the invention, the compound of the formula Iis administered in combination with an inhibitor of liver carnitinepalmitoyltransferase-1 (L-CPT1), as described, for example, inWO2007063012, WO2007096251 (ST-3473), WO2008015081, US2008103182,WO2008074692, WO2008145596, WO2009019199, WO2009156479, WO2010008473.

In another embodiment of the invention, the compound of the formula I isadministered in combination with an inhibitor of carnitinO-palmitoyltransferase II (CPT2), as described, for example, inUS2009270500, US2009270505, WO2009132978, WO2009132979.

In a further embodiment of the invention, the compound of the formula Iis administered in combination with a modulator of serinepalmitoyltransferase (SPT), as described, for example, in WO2008031032,WO2008046071, WO2008083280, WO2008084300.

In one embodiment of the invention, the compound of the formula I isadministered in combination with a squalene synthetase inhibitor, forexample BMS-188494, TAK-475 (lapaquistat acetate), or as described inWO2005077907, JP2007022943, WO2008003424, WO2008132846, WO2008133288,WO2009136396.

In one embodiment of the invention, the compound of the formula I isadministered in combination with ISIS-301012 (mipomersen), an antisenseoligonucleotide which is capable of regulating the apolipoprotein Bgene.

In one embodiment of the invention, the compound of the formula I isadministered in combination with apolipoprotein (ApoB) SNALP, atherapeutic product which comprises an siRNA (directed against the ApoBgene).

In one embodiment of the invention, the compound of the formula I isadministered in combination with a stimulator of the ApoA-1 gene, asdescribed, for example, in WO2008092231.

In one embodiment of the invention, the compound of the formula I isadministered in combination with a modulator of the synthesis ofapolipoprotein C-III, for example ISIS-APOCIIIRx.

In one embodiment of the invention, the compound of the formula I isadministered in combination with an LDL receptor inducer (see U.S. Pat.No. 6,342,512), for example HMR1171, HMR1586, or those as described inWO2005097738, WO2008020607.

In another embodiment of the invention, the compound of the formula I isadministered in combination with an HDL cholesterol-elevating agent, forexample those as described in WO2008040651, WO2008099278, WO2009071099,WO2009086096, US2009247550.

In one embodiment of the invention, the compound of the formula I isadministered in combination with an ABCA1 expression enhancer, asdescribed, for example, in WO2006072393, WO2008062830, WO2009100326.

In one embodiment of the invention, the compound of the formula I isadministered in combination with a lipoprotein lipase modulator, forexample ibrolipim (NO-1886).

In one embodiment of the invention, the compound of the formula I isadministered in combination with a lipoprotein(a) antagonist, forexample gemcabene (CI-1027).

In one embodiment of the invention, the compound of the formula I isadministered in combination with a lipase inhibitor, for exampleorlistat or cetilistat (ATL-962).

In one embodiment of the invention, the compound of the formula I isadministered in combination with an adenosine A1 receptor agonist(adenosine A1 R), for example CVT-3619 or those as described, forexample, in EP1258247, EP1375508, WO2008028590, WO2008077050,WO2009050199, WO2009080197, WO2009100827, WO2009112155.

In one embodiment of the invention, the compound of the formula I isadministered in combination with an adenosine A2B receptor agonist(adenosine A2B R), for example ATL-801.

In another embodiment of the invention, the compound of the formula I isadministered in combination with a modulator of adenosine A2A and/oradenosine A3 receptors, as described, for example, in WO2007111954,WO2007121918, WO2007121921, WO2007121923, WO2008070661, WO2009010871.

In a further embodiment of the invention, the compound of the formula Iis administered in combination with a ligand of the adenosine A1/A2Breceptors, as described, for example, in WO2008064788, WO2008064789,WO2009080198, WO2009100827, WO2009143992.

In one embodiment of the invention, the compound of the formula I isadministered in combination with an adenosine A2B receptor antagonist(adenosine A2B R), as described in US2007270433, WO2008027585,WO2008080461, WO2009037463, WO2009037467, WO2009037468, WO2009118759.

In one embodiment, the compound of the formula I is administered incombination with inhibitors of acetyl-CoA carboxylase (ACC1 and/orACC2), for example those as described in WO199946262, WO200372197,WO2003072197, WO2005044814, WO2005108370, JP2006131559, WO2007011809,WO2007011811, WO2007013691, WO2007095601-603, WO2007119833,WO2008065508, WO2008069500, WO2008070609, WO2008072850, WO2008079610,WO2008088688, WO2008088689, WO2008088692, US2008171761, WO2008090944,JP2008179621, US2008200461, WO2008102749, WO2008103382, WO2008121592,WO2009082346, US2009253725, JP2009196966, WO2009144554, WO2009144555,WO2010003624, WO2010002010.

In another embodiment, the compound of the formula I is administered incombination with modulators of microsomal acyl-CoA:glycerol-3-phosphateacyltransferase 3 (GPAT3, described in WO2007100789) or with modulatorsof microsomal acyl-CoA:glycerol-3-phosphate acyltransferase 4 (GPAT4,described in WO2007100833) or with modulators of mitochondrialglycerol-3-phosphate O-acyltransferase, described in WO2010005922.

In a further embodiment, the compound of the formula I is administeredin combination with modulators of xanthine oxidoreductase (XOR).

In another embodiment, the compound of the formula I is administered incombination with inhibitors of soluble epoxide hydrolase (sEH), asdescribed, for example, in WO2008051873, WO2008051875, WO2008073623,WO2008094869, WO2008112022, WO2009011872, WO2009049154, WO2009049157,WO2009049165, WO2009073772, WO2009097476, WO2009111207, WO2009129508,WO2009151800.

In a further embodiment, the compound of the formula I is administeredin combination with CART modulators (see “Cocaine-amphetamine-regulatedtranscript influences energy metabolism, anxiety and gastric emptying inmice” Asakawa, A. et al.: Hormone and Metabolic Research (2001), 33(9),554-558);

NPY antagonists, for example4-[(4-aminoquinazolin-2-ylamino)methyl]-cyclohexylmethylnaphthalene-1-sulfonamidehydrochloride (CGP 71683A) or velneperit or those as described inWO2009110510;

NPY-5 receptor antagonists/receptor modulators, such as L-152804 or thecompound “NPY-5-BY” from Banyu, or as described, for example, inWO2006001318, WO2007103295, WO2007125952, WO2008026563, WO2008026564,WO2008052769, WO2008092887, WO2008092888, WO2008092891, WO2008129007,WO2008134228, WO2009054434, WO2009095377, WO2009131096;

NPY-4 receptor antagonists, as described, for example, in WO2007038942;

NPY-2 receptor antagonists/modulators, as described, for example, inWO2007038943, WO2009006185, US2009099199, US2009099243, US2009099244,WO2009079593, WO2009079597;

peptide YY 3-36 (PYY3-36) or analogous compounds, for example CJC-1682(PYY3-36 conjugated with human serum albumin via Cys34) or CJC-1643(derivative of PYY3-36, which is conjugated in vivo to serum albumin),or those as described in WO2005080424, WO2006095166, WO2008003947,WO2009080608;

NPY-2 receptor agonists, as described, for example, in WO2009080608;derivatives of the peptide obestatin, as described by WO2006096847;

CB1R (cannabinoid receptor 1) antagonists/inverse agonists, for examplerimonabant, surinabant (SR147778), SLV-319 (ibipinabant), AVE-1625,taranabant (MK-0364) or salts thereof, otenabant (CP-945,598),rosonabant, V-24343 or those compounds as described in, for example, EP0656354, WO 00/15609, WO2001/64632-64634, WO 02/076949, WO2005080345,WO2005080328 WO2005080343, WO2005075450, WO2005080357, WO200170700,WO2003026647-48, WO200302776, WO2003040107, WO2003007887, WO2003027069,U.S. Pat. No. 6,509,367, WO200132663, WO2003086288, WO2003087037,WO2004048317, WO2004058145, WO2003084930, WO2003084943, WO2004058744,WO2004013120, WO2004029204, WO2004035566, WO2004058249, WO2004058255,WO2004058727, WO2004069838, US20040214837, US20040214855, US20040214856,WO2004096209, WO2004096763, WO2004096794, WO2005000809, WO2004099157,US20040266845, WO2004110453, WO2004108728, WO2004000817, WO2005000820,US20050009870, WO200500974, WO2004111033-34, WO200411038-39,WO2005016286, WO2005007111, WO2005007628, US20050054679, WO2005027837,WO2005028456, WO2005063761-62, WO2005061509, WO2005077897, WO2006018662,WO2006047516, WO2006060461, WO2006067428, WO2006067443, WO2006087480,WO2006087476, WO2006100208, WO2006106054, WO2006111849, WO2006113704,WO2007009705, WO2007017124, WO2007017126, WO2007018459, WO2007018460,WO2007016460, WO2007020502, WO2007026215, WO2007028849, WO2007031720,WO2007031721, WO2007036945, WO2007038045, WO2007039740, US20070015810,WO2007046548, WO2007047737, WO2007057687, WO2007062193, WO2007064272,WO2007079681, WO2007084319, WO2007084450, WO2007086080, EP1816125,US2007213302, WO2007095513, WO2007096764, US2007254863, WO2007119001,WO2007120454, WO2007121687, WO2007123949, US2007259934, WO2007131219,WO2007133820, WO2007136571, WO2007136607, WO2007136571, U.S. Pat. No.7,297,710, WO2007138050, WO2007139464, WO2007140385, WO2007140439,WO2007146761, WO2007148061, WO2007148062, US2007293509, WO2008004698,WO2008017381, US2008021031, WO2008024284, WO2008031734, WO2008032164,WO2008034032, WO2008035356, WO2008036021, WO2008036022, WO2008039023,WO2998043544, WO2008044111, WO2008048648, EP1921072-A1, WO2008053341,WO2008056377, WO2008059207, WO2008059335, WO2008062424, WO2008068423,WO2008068424, WO2008070305, WO2008070306, WO2008074816, WO2008074982,WO2008075012, WO2008075013, WO2008075019, WO2008075118, WO2008076754,WO2008081009, WO2008084057, EP1944295, US2008090809, US2008090810,WO2008092816, WO2008094473, WO2008094476, WO2008099076, WO2008099139,WO2008101995, US2008207704, WO2008107179, WO2008109027, WO2008112674,WO2008115705, WO2008118414, WO2008119999, WO200812000, WO2008121257,WO2008127585, WO2008129157, WO2008130616, WO2008134300, US2008262066,US2008287505, WO2009005645, WO2009005646, WO2009005671, WO2009023292,WO2009023653, WO2009024819, WO2009033125, EP2042175,WO2009053548-WO2009053553, WO2009054923, WO2009054929, WO2009059264,WO2009073138, WO2009074782, WO2009075691, WO2009078498, WO2009087285,WO2009074782, WO2009097590, WO2009097995, WO2009097996, WO2009097998,WO2009097999, WO2009098000, WO2009106708, US2009239909, WO2009118473,US2009264436, US2009264476, WO2009130234, WO2009131814, WO2009131815,US2009286758, WO2009141532, WO2009141533, WO2009153569, WO2010003760,WO2010012437, WO2010019762;

cannabinoid receptor 1/cannabinoid receptor 2 (CB1/CB2) modulatingcompounds, for example delta-9-tetrahydrocannabivarin, or those asdescribed, for example, in WO2007001939, WO2007044215, WO2007047737,WO2007095513, WO2007096764, WO2007112399, WO2007112402, WO2008122618,WO2009007697, WO2009012227, WO2009087564, WO2009093018, WO2009095752,WO2009120660, WO2010012964;

cannabinoid receptor 2 (CB2) modulating compounds, for example those asdescribed, for example, in WO2008063625, WO2008157500, WO2009004171,WO2009032754, WO2009055357, WO2009061652, WO2009063495, WO2009067613,WO2009114566;

modulators of FAAH (fatty acid amide hydrolase), as described, forexample, in WO2007140005, WO2008019357, WO2008021625, WO2008023720,WO2008030532, WO2008129129, WO2008145839, WO2008145843, WO2008147553,WO2008153752, WO2009011904, WO2009048101, WO2009084970, WO2009105220,WO2009109504, WO2009109743, WO2009117444, WO2009127944, WO2009138416,WO2009151991, WO2009152025, WO2009154785, WO2010005572, WO2010017079;

inhibitors of fatty acid synthase (FAS), as described, for example, inWO2008057585, WO2008059214, WO2008075064, WO2008075070, WO2008075077,WO2009079860;

inhibitors of LCE (long chain fatty acid elongase)/long chain fatty acidCoA ligase, as described, for example, in WO2008120653, WO2009038021,WO2009044788, WO2009081789, WO2009099086;

vanilloid-1 receptor modulators (modulators of TRPV1), as described, forexample, in WO2007091948, WO2007129188, WO2007133637, WO2008007780,WO2008010061, WO2008007211, WO2008010061, WO2008015335, WO2008018827,WO2008024433, WO2008024438, WO2008032204, WO2008050199, WO2008059339,WO2008059370, WO2008066664, WO2008075150, WO2008090382, WO2008090434,WO2008093024, WO2008107543, WO2008107544, WO2008110863, WO2008125295,WO2008125296, WO2008125337, WO2008125342, WO2008132600, WO2008133973,WO2009010529, WO2009010824, WO2009016241, WO2009023539, WO2009038812,WO2009050348, WO2009055629, WO2009055749, WO2009064449, WO2009081222,WO2009089057, WO2009109710WO2009112677, WO2009112678, WO2009112679,WO2009121036, WO2009124551, WO2009136625, WO2010002209;

modulators, ligands, antagonists or inverse agonists of the opioidreceptors, for example GSK-982 or those as described, for example, inWO2007047397, WO2008021849, WO2008021851, WO2008032156, WO2008059335,WO2008125348, WO2008125349, WO2008142454, WO2009030962, WO2009103552,WO2009115257;

modulators of the “orphan opioid (ORL-1) receptor”, as described, forexample, in US2008249122, WO2008089201;

agonists of the prostaglandin receptor, for example bimatoprost or thosecompounds as described in WO2007111806;

MC4 receptor agonists (melanocortin-4 receptor agonists, MC4R agonists,for exampleN-[2-(3a-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydro-pyrazolo[4,3-c]pyridin-5-yl)-1-(4-chlorophenyl)-2-oxoethyl]-1-amino-1,2,3,4-tetrahydronaphthalene-2-carboxamide;(WO 01/91752)) or LB53280, LB53279, LB53278 or THIQ, MB243, RY764,CHIR-785, PT-141, MK-0493, or those as described in WO2005060985,WO2005009950, WO2004087159, WO2004078717, WO2004078716, WO2004024720,US20050124652, WO2005051391, WO2004112793, WOUS20050222014,US20050176728, US20050164914, US20050124636, US20050130988,US20040167201, WO2004005324, WO2004037797, WO2004089307, WO2005042516,WO2005040109, WO2005030797, US20040224901, WO200501921, WO200509184,WO2005000339, EP1460069, WO2005047253, WO2005047251, WO2005118573,EP1538159, WO2004072076, WO2004072077, WO2006021655-57, WO2007009894,WO2007015162, WO2007041061, WO2007041052, JP2007131570, EP-1842846,WO2007096186, WO2007096763, WO2007141343, WO2008007930, WO2008017852,WO2008039418, WO2008087186, WO2008087187, WO2008087189,WO2008087186-WO2008087190, WO2008090357, WO2008142319, WO2009015867,WO2009061411, US2009076029, US2009131465, WO2009071101, US2009305960,WO2009144432, WO2009151383 WO2010015972;

MC4 receptor modulators (melanocortin-4 receptor modulators), asdescribed, for example, in WO2009010299, WO2009074157;

orexin receptor 1 antagonists (OX1R antagonists), orexin receptor 2antagonists (OX2R antagonists) or mixed OX1R/OX2R antagonists (e.g.1-(2-methylbenzoxazol-6-yl)-3-[1,5]naphthyridin-4-ylurea hydrochloride(SB-334867-A), or those as described, for example, in WO200196302,WO200185693, WO2004085403, WO2005075458, WO2006067224, WO2007085718,WO2007088276, WO2007116374, WO2007122591, WO2007126934, WO2007126935,WO2008008517, WO2008008518, WO2008008551, WO2008020405, WO2008026149,WO2008038251, US2008132490, WO2008065626, WO2008078291, WO2008087611,WO2008081399, WO2008108991, WO2008107335, US2008249125, WO2008147518,WO2008150364, WO2009003993, WO2009003997, WO2009011775, WO2009016087,WO2009020642, WO2009058238, US2009186920, US2009203736, WO2009092642,WO2009100994, WO2009104155, WO2009124956, WO2009133522, WO2009156951,WO2010017260);

histamine H3 receptor antagonists/inverse agonists (e.g.3-cyclohexyl-1-(4,4-dimethyl-1,4,6,7-tetrahydroimidazo[4,5-c]pyridin-5-yl)propan-1-oneoxalic acid salt (WO 00/63208), or those as described in WO200064884,WO2005082893, WO2005123716, US2005171181 (e.g. PF-00389027),WO2006107661, WO2007003804, WO2007016496, WO2007020213, WO2007049798,WO2007055418, WO2007057329, WO2007062999, WO2007065820, WO2007068620,WO2007068641, WO2007075629, WO2007080140, WO2007082840, WO2007088450,WO2007088462, WO2007094962, WO2007099423, WO2007100990, WO2007105053,WO2007106349, WO2007110364, WO2007115938, WO2007131907, WO2007133561,US2007270440, WO2007135111, WO2007137955, US2007281923, WO2007137968,WO2007138431, WO2007146122, WO2008005338, WO2008012010, WO2008015125,WO2008045371, EP1757594, WO2008068173, WO2008068174, US20080171753,WO2008072703, WO2008072724, US2008188484, US2008188486, US2008188487,WO2008109333, WO2008109336, WO2008126886, WO2008154126, WO2008151957,US2008318952, WO2009003003, WO2009013195, WO2009036132, WO2009039431,WO2009045313, WO2009058300, WO2009063953, WO2009067401, WO2009067405,WO2009067406, US2009163464, WO2009100120, WO2009105206, WO2009121812,WO2009126782, WO2010011653, WO2010011657);

histamine H1/histamine H3 modulators, for example betahistine or itsdihydrochloride;

modulators of the histamine H3 transporter or of the histamineH3/serotonin transporter, as described, for example, in WO2008002816,WO2008002817, WO2008002818, WO2008002820;

modulators of vesicular monoamine transporter 2 (VMAT2), as described,for example, in WO2009126305;

histamine H4 modulators, as described, for example, in WO2007117399,US2009156613;

CRF antagonists (e.g.[2-methyl-9-(2,4,6-trimethylphenyl)-9H-1,3,9-triazafluoren-4-yl]dipropylamine(WO 00/66585) or those CRF1 antagonists as described in WO2007105113,WO2007133756, WO2008036541, WO2008036579, WO2008083070, WO2010015628,WO2010015655);

CRF BP antagonists (e.g. urocortin);

urocortin agonists;

modulators of the beta-3 adrenoceptor, for example1-(4-chloro-3-methanesulfonylmethylphenyl)-2-[2-(2,3-dimethyl-1H-indol-6-yloxy)ethylamino]ethanolhydrochloride (WO 01/83451) or solabegron (GW-427353) or N-5984(KRP-204), or those as described in JP2006111553, WO2002038543,WO2002038544, WO2007048840-843, WO2008015558, EP1947103, WO2008132162;

MSH (melanocyte-stimulating hormone) agonists;

MCH (melanine-concentrating hormone) receptor antagonists (for exampleNBI-845, A-761, A-665798, A-798, ATC-0175, T-226296, T-71 (AMG-071,AMG-076), GW-856464, NGD-4715, ATC-0453, ATC-0759, GW-803430, or thosecompounds as described in WO2005085200, WO2005019240, WO2004011438,WO2004012648, WO2003015769, WO2004072025, WO2005070898, WO2005070925,WO2004039780, WO2004092181, WO2003033476, WO2002006245, WO2002089729,WO2002002744, WO2003004027, FR2868780, WO2006010446, WO2006038680,WO2006044293, WO2006044174, JP2006176443, WO2006018280, WO2006018279,WO2006118320, WO2006130075, WO2007018248, WO2007012661, WO2007029847,WO2007024004, WO2007039462, WO2007042660, WO2007042668, WO2007042669,US2007093508, US2007093509, WO2007048802, JP2007091649, WO2007092416;WO2007093363-366, WO2007114902, WO2007114916, WO2007141200,WO2007142217, US2007299062, WO2007146758, WO2007146759, WO2008001160,WO2008016811, WO2008020799, WO2008022979, WO2008038692, WO2008041090,WO2008044632, WO2008047544, WO2008061109, WO2008065021, WO2008068265,WO2008071646, WO2008076562, JP2008088120, WO2008086404, WO2008086409,US2008269110, WO2008140239, WO2009021740, US2009011994, US2009082359,WO2009041567, WO2009076387, WO2009089482, WO2009103478, WO2009119726,WO2009120655, WO2009123194, WO2009137270, WO2009146365, WO2009154132);

CCK-A (CCK-1) agonists/modulators (for example{2-[4-(4-chloro-2,5-dimethoxy-phenyl)-5-(2-cyclohexylethyl)thiazol-2-ylcarbamoyl]-5,7-dimethylindol-1-yl}aceticacid trifluoroacetic acid salt (WO 99/15525) or SR-146131 (WO 0244150)or SSR-125180), or those as described in WO2005116034, WO2007120655,WO2007120688, WO2007120718, WO2008091631;

serotonin reuptake inhibitors (e.g. dexfenfluramine), or those asdescribed in WO2007148341, WO2008034142, WO2008081477, WO2008120761,WO2008141081, WO2008141082, WO2008145135, WO2008150848, WO2009043834,WO2009077858;

mixed serotonin/dopamine reuptake inhibitors (e.g. bupropion), or thoseas described in WO2008063673, or solid combinations of bupropion withnaltrexone or bupropion with zonisamide;

mixed reuptake inhibitors, for example DOV-21947 or those as describedin WO2009016214, WO2009016215, WO2009077584, WO2009098208, WO2009098209,WO2009106769, WO2009109517, WO2009109518, WO2009109519, WO2009109608,WO2009145357, WO2009149258;

mixed serotoninergic and noradrenergic compounds (e.g. WO 00/71549);

5-HT receptor agonists, for example 1-(3-ethylbenzofuran-7-yl)piperazineoxalic acid salt (WO 01/09111);

mixed dopamine/norepinephrine/acetylcholine reuptake inhibitors (e.g.tesofensine), or those as described, for example, in WO2006085118,WO2008150480;

dopamine antagonists, as described, for example, in WO2008079838,WO2008079839, WO2008079847, WO2008079848;

norepinephrine reuptake inhibitors, as described, for example, inUS2008076724, WO2009062318;

5-HT1A receptor modulators, as described, for example, in WO2009006227,WO2009137679, WO2009137732;

5-HT2A receptor antagonists, as described, for example, in WO2007138343;

5-HT2C receptor agonists (for example lorcaserine hydrochloride(APD-356) or BVT-933, or those as described in WO200077010,WO200077001-02, WO2005019180, WO2003064423, WO200242304, WO2005035533,WO2005082859, WO2006004937, US2006025601, WO2006028961, WO2006077025,WO2006103511, WO2007028132, WO2007084622, US2007249709; WO2007132841,WO2007140213, WO2008007661, WO2008007664, WO2008009125, WO2008010073,WO2008108445, WO2009063991, WO2009063992, WO2009063993, WO2009079765);

5-HT6 receptor modulators, for example E-6837, BVT-74316, PF-3246799 orPRX-07034, or those as described, for example, in WO2005058858,WO2007054257, WO2007107373, WO2007108569, WO2007108742-744,WO2008003703, WO2008027073, WO2008034815, WO2008054288, EP1947085,WO2008084491, WO2008084492, WO2008092665, WO2008092666, WO2008101247,WO2008110598, WO2008116831, WO2008116833, WO2008117169, WO2008136017,WO2008147812, EP2036888, WO2009013010, WO2009034581, WO2009053997,WO2009056632, WO2009073118, WO2009115515, WO2009135925, WO2009135927,WO2010000456, WO2010012806, EP2145887;

agonists of estrogen receptor gamma (ERRγ agonists), as described, forexample, in WO2007131005, WO2008052709;

agonists of estrogen receptor alpha (ERRα/ERR1 agonists), as described,for example, in WO2008109727;

agonists of estrogen receptor beta (ERRβ agonists), as described, forexample, in WO2009055734, WO2009100335, WO2009127686;

sigma-1 receptor antagonists, as described, for example, inWO2007098953, WO2007098961, WO2008015266, WO2008055932, WO2008055933,WO2009071657;

muscarin 3 receptor (M3R) antagonists, as described, for example, inWO2007110782, WO2008041184;

bombesin receptor agonists (BRS-3 agonists), as described, for example,in WO2008051404, WO2008051405, WO2008051406, WO2008073311;

galanin receptor antagonists;

growth hormone (e.g. human growth hormone or ADD-9604);

growth hormone releasing compounds (tert-butyl6-benzyloxy-1-(2-diisopropylaminoethylcarbamoyl)-3,4-dihydro-1H-isoquinoline-2-carboxylate(WO 01/85695));

growth hormone secretagogue receptor antagonists (ghrelin antagonists),for example A-778193, or those as described in WO2005030734,WO2007127457, WO2008008286, WO2009056707;

growth hormone secretagogue receptor modulators (ghrelin modulators),for example JMV-2959, JMV-3002, JMV-2810, JMV-2951, or those asdescribed in WO2006012577 (e.g. YIL-781 or YIL-870), WO2007079239,WO2008092681, WO2008145749, WO2008148853, WO2008148854, WO2008148856,WO2009047558, WO2009071283, WO2009115503;

TRH agonists (see, for example, EP 0 462 884);

decoupling protein 2 or 3 modulators (as described, for example, inWO2009128583);

chemical decouplers (e.g. WO2008059023, WO2008059024, WO2008059025,WO2008059026);

leptin receptor agonists (see, for example, Lee, Daniel W.; Leinung,Matthew C.; Rozhayskaya-Arena, Marina; Grasso, Patricia. Leptin agonistsas a potential approach to the treatment of obesity. Drugs of the Future(2001), 26(9), 873-881);

leptin receptor modulators, as described, for example, in WO2009019427,WO2009071658, WO2009071668, WO2009071677, WO2009071678, WO2009147211,WO2009147216, WO2009147219, WO2009147221;

DA agonists (bromocriptin, bromocriptin mesylate, doprexin) or those asdescribed in US2009143390;

lipase/amylase inhibitors (e.g. WO 00/40569, WO2008107184, WO2009049428WO2009125819);

inhibitors of diacylglycerol O-acyltransferases (DGATs), for exampleBAY-74-4113, or as described, for example, in US2004/0224997,WO2004094618, WO200058491, WO2005044250, WO2005072740, JP2005206492,WO2005013907, WO2006004200, WO2006019020, WO2006064189, WO2006082952,WO2006120125, WO2006113919, WO2006134317, WO2007016538, WO2007060140,JP2007131584, WO2007071966, WO2007126957, WO2007137103, WO2007137107,WO2007138304, WO2007138311, WO2007141502, WO2007141517, WO2007141538,WO2007141545, WO2007144571, WO2008011130, WO2008011131, WO2008039007,WO2008048991, WO2008067257, WO2008099221, WO2008129319, WO2008141976,WO2008148840, WO2008148849, WO2008148851, WO2008148868, WO2009011285,WO2009016462, WO2009024821, US2009076275, WO2009040410, WO2009071483,WO2009081195, WO2009119534, WO2009126624, WO2009126861, WO2010007046,WO2010017040;

inhibitors of monoacylglycerol acyltransferase (2-acylglycerolO-acyltransferase; MGAT), as described, for example, in WO2008038768;

inhibitors of fatty acid synthase (FAS), for example C75, or those asdescribed in WO2004005277, WO2008006113;

inhibitors of stearoyl-CoA delta9 desaturase (SCD1), as described, forexample, in WO2007009236, WO2007044085, WO2007046867, WO2007046868,WO20070501124, WO2007056846, WO2007071023, WO2007130075, WO2007134457,WO2007136746, WO2007143597, WO2007143823, WO2007143824, WO2008003753,WO2008017161, WO2008024390, WO2008029266, WO2008036715, WO2008043087,WO2008044767, WO2008046226, WO2008056687, WO2008062276, WO2008064474,WO2008074824, WO2008074832, WO2008074833, WO2008074834, WO2008074835,WO2008089580, WO2008096746, WO2008104524, WO2008116898, US2008249100,WO2008120744, WO2008120759, WO2008123469, WO2008127349, WO2008128335,WO2008135141, WO2008139845, WO2008141455, US20080255130, US2008255161,WO2008141455, WO2009010560, WO2009016216, WO2009012573, WO2009024287,JP2009019013, WO2009037542, WO2009056556, WO2009060053, WO2009060054,WO2009070533, WO2009073973, WO2009103739, WO2009117659, WO2009117676,US2009253693, US2009253738, WO2009124259, WO2009126123, WO2009126527,WO2009129625, WO2009137201, WO2009150196, WO2009156484, WO2010006962,WO2010007482;

inhibitors of fatty acid desaturase 1 (delta5 desaturase), as described,for example, in WO2008089310;

inhibitors of monoglyceride lipase (MGL), as described in WO2008145842;

hypoglycemic/hypertriglyceridemic indoline compounds, as described inWO2008039087, WO2009051119;

inhibitors of “adipocyte fatty acid-binding protein aP2”, for exampleBMS-309403 or those as described in WO2009028248;

activators of adiponectin secretion, as described, for example, inWO2006082978, WO2008105533, WO2008136173;

promoters of adiponectin production, as described, for example, inWO2007125946, WO2008038712;

modified adiponectins, as described, for example, in WO2008121009;

oxyntomodulin or analogs thereof (for example, TKS-1225);

oleoyl-estrone

or agonists or partial agonists of the thyroid hormone receptor (thyroidhormone receptor agonists), for example: KB-2115 (eprotirome), QRX-431(sobetirome) or DITPA, or those as described in WO20058279, WO200172692,WO200194293, WO2003084915, WO2004018421, WO2005092316, WO2007003419,WO2007009913, WO2007039125, WO2007110225, WO2007110226, WO2007128492,WO2007132475, WO2007134864, WO2008001959, WO2008106213, JP2009155261;

or agonists of the thyroid hormone receptor beta (TR-beta), for exampleMB-07811 or MB-07344, or those as described in WO2008062469.

In one embodiment of the invention, the compound of the formula I isadministered in combination with a combination of eprotirome withezetimibe.

In one embodiment of the invention, the compound of the formula I isadministered in combination with an inhibitor of site-1 protease (S1P),for example PF-429242.

In a further embodiment of the invention, the compound of the formula Iis administered in combination with a modulator of the “trace amineassociated receptor 1” (TAAR1), as described, for example, inUS2008146523, WO2008092785.

In one embodiment of the invention, the compound of the formula I isadministered in combination with an inhibitor of growth factor receptorbound protein 2 (GRB2), as described, for example, in WO2008067270.

In a further embodiment of the invention, the compound of the formula Iis administered in combination with an RNAi (siRNA) therapeutic agentdirected against PCSK9 (proprotein convertase subtilisin/kexin type 9).

In one embodiment, the compound of the formula I is administered incombination with Omacor® or Lovaza™ (omega-3 fatty acid ester; highlyconcentrated ethyl ester of eicosapentaenoic acid and of docosahexaenoicacid).

In one embodiment, the compound of the formula I is administered incombination with lycopene.

In one embodiment of the invention, the compound of the formula I isadministered in combination with an antioxidant, for example OPC-14117,AGI-1067 (succinobucol), probucol, tocopherol, ascorbic acid, β-caroteneor selenium, or those as described in WO2009135918.

In one embodiment of the invention, the compound of the formula I isadministered in combination with a vitamin, for example vitamin B6 orvitamin B12.

In one embodiment, the compound of the formula I is administered incombination with more than one of the aforementioned compounds, forexample in combination with a sulfonylurea and metformin, a sulfonylureaand acarbose, repaglinide and metformin (PrandiMet™), insulin and asulfonylurea, insulin and metformin, insulin and troglitazone, insulinand lovastatin, etc.

In a further embodiment, the compound of the formula I is administeredin combination with an activator of soluble guanylate cyclase (sGC), asdescribed, for example, in WO2009032249.

In another embodiment, the compound of the formula I is administered incombination with an inhibitor of carboanhydrase type 2 (carbonicanhydrase type 2), for example those as described in WO2007065948,WO2009050252.

In another embodiment, the compound of the formula I is administered incombination with topiramat or a derivative thereof, as described inWO2008027557, US2009304789.

In a further embodiment, the compound of the formula I is administeredin combination with a solid combination of topiramat with phentermin(Qnexa™).

In a further embodiment, the compound of the formula I is administeredin combination with an antisense compound, e.g. ISIS-377131, whichinhibits the production of the glucocorticoid receptor.

In another embodiment, the compound of the formula I is administered incombination with an aldosterone synthase inhibitor and an antagonist ofthe glucocorticoid receptor, a cortisol synthesis inhibitor and/or anantagonist of the corticotropin releasing factor, as described, forexample, in EP1886695, WO2008119744.

In one embodiment, the compound of the formula I is administered incombination with an agonist of the RUP3 receptor, as described, forexample, in WO2007035355, WO2008005576.

In another embodiment, the compound of the formula I is administered incombination with an activator of the gene which codes for ataxiatelangiectasia mutated (ATM) protein kinase, for example chloroquine.

In one embodiment, the compound of the formula I is administered incombination with a tau protein kinase 1 inhibitor (TPK1 inhibitor), asdescribed, for example, in WO2007119463, WO2009035159, WO2009035162.

In one embodiment, the compound of the formula I is administered incombination with a “c-Jun N-terminal kinase” inhibitor (JNK inhibitor),for example B1-78D3 or those as described, for example, in WO2007125405,WO2008028860, WO2008118626.

In one embodiment, the compound of the formula I is administered incombination with an endothelin A receptor antagonist, for exampleavosentan (SPP-301).

In one embodiment, the compound of the formula I is administered incombination with inhibitors of neutral endopeptidase (NEP inhibitors),as described, for example, in WO2009138122, WO2009135526.

In one embodiment, the compound of the formula is administered incombination with modulators of the glucocorticoid receptor (GR), forexample KB-3305 or those compounds as described, for example, inWO2005090336, WO2006071609, WO2006135826, WO2007105766, WO2008120661,WO2009040288, WO2009058944, WO2009108525, WO2009111214.

In one embodiment, the further active ingredient is vareniclinetartrate, a partial agonist of the alpha 4-beta 2 nicotinicacetylcholine receptor.

In one embodiment, the further active ingredient is an agonist of thealpha 7-nicotinic acetylcholine receptor, as described, for example, inWO2009018551, WO2009071519, WO2009071576, WO2009071577.

In one embodiment, the further active ingredient is trodusquemine.

In one embodiment, the further active ingredient is a modulator of theenzyme SIRT1 and/or SIRT3 (an NAD⁺-dependent protein deacetylase); thisactive ingredient may, for example, be resveratrol in suitableformulations, or those compounds as specified in WO2007019416 (e.g.SRT-1720), WO2008073451, WO2008156866, WO2008156869, WO2009026701,WO2009049018, WO2009058348, WO2009061453, WO2009134973, WO2009146358,WO2010003048.

In one embodiment of the invention, the further active ingredient isDM-71 (N-acetyl-L-cysteine with bethanechol).

In one embodiment, the compound of the formula is administered incombination with antihypercholesterolemic compounds, as described, forexample, in WO2004000803, WO2006000804, WO2004000805, WO2004087655,WO2005113496, WO2007059871, WO2007107587, WO2007111994, WO2008052658,WO2008106600, WO2008113796, US2008280836, WO2009113952, US2009312302.

In a further embodiment, the compound of the formula I is administeredin combination with inhibitors of SREBP (sterol regulatoryelement-binding protein), for example fatostatin, or those as described,for example, in WO2008097835.

In another embodiment, the compound of the formula I is administered incombination with a cyclic peptide agonist of the VPAC2 receptor, asdescribed, for example, in WO2007101146, WO2007133828.

In a further embodiment, the compound of the formula I is administeredin combination with an agonist of the endothelin receptor, as described,for example, in WO2007112069.

In a further embodiment, the compound of the formula I is administeredin combination with AKP-020 (bis(ethylmaltolato)oxovanadium(IV)).

In another embodiment, the compound of the formula I is administered incombination with tissue-selective androgen receptor modulators (SARM),as described, for example, in WO2007099200, WO2007137874.

In a further embodiment, the compound of the formula I is administeredin combination with an AGE (advanced glycation endproduct) inhibitor, asdescribed, for example, in JP2008024673.

In one embodiment of the invention, the further active ingredient isleptin; see, for example, “Perspectives in the therapeutic use ofleptin”, Salvador, Javier; Gomez-Ambrosi, Javier; Fruhbeck, Gema, ExpertOpinion on Pharmacotherapy (2001), 2(10), 1615-1622.

In another embodiment of the invention, the further active ingredient ismetreleptin (recombinant methionyl-leptin) combined with pramlintide.

In a further embodiment of the invention, the further active ingredientis the tetrapeptide ISF-402.

In one embodiment, the further active ingredient is dexamphetamine oramphetamine.

In one embodiment, the further active ingredient enfluramine ordexfenfluramine.

In another embodiment, the further active ingredient is sibutramine orthose derivatives as described in WO2008034142.

In one embodiment, the further active ingredient is mazindol orphentermin.

In a further embodiment, the further active ingredient is geniposidicacid (WO2007100104) or derivatives thereof (JP2008106008).

In another embodiment, the further active ingredient is a neuropeptideFF2 agonist, as described, for example, in WO2009038012.

In one embodiment, the further active ingredient is a nasal calciumchannel blocker, for example diltiazem, or those as described in U.S.Pat. No. 7,138,107.

In one embodiment, the further active ingredient is an inhibitor ofsodium-calcium ion exchange, for example those as described inWO2008028958, WO2008085711.

In a further embodiment, the further active ingredient is a blocker ofcalcium channels, for example of CaV3.2 or CaV2.2, as described inWO2008033431, WO2008033447, WO2008033356, WO2008033460, WO2008033464,WO2008033465, WO2008033468, WO2008073461.

In one embodiment, the further active ingredient is a modulator of acalcium channel, for example those as described in WO2008073934,WO2008073936, WO2009107660.

In one embodiment, the further active ingredient is an inhibitor of thecalcium metabolism, for example those as described in US2009124680.

In one embodiment, the further active ingredient is a blocker of the“T-type calcium channel”, as described, for example, in WO2008033431,WO2008110008, US2008280900, WO2008141446, US2009270338, WO2009146540,US2009325979, WO2009146539.

In one embodiment, the further active ingredient is an inhibitor of KCNQpotassium channel 2 or 3, for example those as described inUS2008027049, US2008027090.

In one embodiment, the further active ingredient is a modulator of KCNNpotassium channel 1, 2 or 3 (modulators of the SK1, SK2 and/or SK3channel), for example those as described in US2009036475.

In one embodiment, the further active ingredient is an inhibitor of thepotassium Kv1.3 ion channel, for example those as described inWO2008040057, WO2008040058, WO2008046065, WO2009043117.

In one embodiment, the further active ingredient is a potassium channelmodulator, for example those as described in WO2008135447, WO2008135448,WO2008135591, WO2009099820.

In a further embodiment, the further active ingredient is ahyperpolarization-activated cyclic nucleotide-gated (HCN)potassium-sodium channel inhibitor, for example those as described inUS2009069296.

In another embodiment, the further active ingredient is an inhibitor ofthe sodium-potassium-2 chloride (NKCCl) cotransporter, for example thoseas described in WO2009130735.

In another embodiment, the further active ingredient is a voltage-gatedsodium channel inhibitor, for example those as described inWO2009049180, WO2009049181.

In another embodiment, the further active ingredient is a modulator ofthe MCP-1 receptor (monocyte chemoattractant protein-1 (MCP-1)), forexample those as described in WO2008014360, WO2008014381.

In one embodiment, the further active ingredient is a modulator ofsomatostatin receptor 3 (SSTR3), for example those as described inWO2009011836.

In one embodiment, the further active ingredient is a modulator ofsomatostatin receptor 5 (SSTR5), for example those as described inWO2008019967, US2008064697, US2008249101, WO2008000692, US2008293756,WO2008148710.

In one embodiment, the further active ingredient is a modulator ofsomatostatin receptor 2 (SSTR2), for example those as described inWO2008051272.

In one embodiment, the further active ingredient is a compound which iscapable of reducing the amount of retinol-binding protein 4 (RBP4), forexample those as described in WO2009051244, WO2009145286.

In one embodiment, the further active ingredient is anerythropoietin-mimetic peptide which acts as an erythropoietin (EPO)receptor agonist. Such molecules are described, for example, inWO2008042800.

In a further embodiment, the further active ingredient is an anorectic/ahypoglycemic compound, for example those as described in WO2008035305,WO2008035306, WO2008035686.

In one embodiment, the further active ingredient is an inductor oflipoic acid synthetase, for example those as described in WO2008036966,WO2008036967.

In one embodiment, the further active ingredient is a stimulator ofendothelial nitric oxide synthase (eNOS), for example those as describedin WO2008058641, WO2008074413.

In one embodiment, the further active ingredient is a modulator ofcarbohydrate and/or lipid metabolism, for example those as described inWO2008059023, WO2008059024, WO2008059025, WO2008059026.

In a further embodiment, the further active ingredient is an angiotensinII receptor antagonist, for example those as described in WO2008062905,WO2008067378, WO2008062905.

In one embodiment, the further active ingredient is an agonist of thesphingosine 1-phosphate receptor (S1P), for example those as describedin WO2008064315, WO2008074820, WO2008074821, WO2008135522, WO2009019167,WO2009043013, WO2009080663, WO2009085847, WO20091 51529, WO2009151621,WO2009151626, WO2009154737.

In one embodiment, the further active ingredient is an agent whichretards gastric emptying, for example 4-hydroxyisoleucine(WO2008044770).

In one embodiment, the further active ingredient is atrytophan-5-hydroxylase inhibitor-1 (TPH1 inhibitor), which modulatesgastrointestinal motility, as described, for example, in WO2009014972.

In one embodiment, the further active ingredient is a muscle-relaxingsubstance, as described, for example, in WO2008090200.

In a further embodiment, the further active ingredient is an inhibitorof monoamine oxidase B (MAO-B), for example those as described inWO2008092091, WO2009066152.

In a further embodiment, the further active ingredient is an inhibitorof monoamine oxidase A (MAO-A), for example those as described inWO2009030968.

In another embodiment, the further active ingredient is an inhibitor ofthe binding of cholesterol and/or triglycerides to the SCP-2 protein(sterol carrier protein-2), for example those as described inUS2008194658.

In a further embodiment, the further active ingredient is a compoundwhich binds to the β-subunit of the trimeric GTP-binding protein, forexample those as described in WO2008126920.

In one embodiment, the further active ingredient is a urate anionexchanger inhibitor 1, as described, for example, in WO2009070740.

In one embodiment, the further active ingredient is a modulator of theATP transporter, as described, for example, in WO2009108657.

In another embodiment, the further active ingredient is lisofylline,which prevents autoimmune damage to insulin-producing cells.

In yet another embodiment, the further active ingredient is an extractfrom Bidens pilosa with the ingredient cytopiloyne as described inEP1955701.

In one embodiment, the further active ingredient is an inhibitor ofglucosylceramide synthase, as described, for example, in WO2008150486.

In a further embodiment of the invention, the further active ingredientis a glycosidase inhibitor, as described, for example, in WO2009117829,WO2009155753.

In another embodiment, the further active ingredient is an ingredientfrom the plant Hoodia Gordonii, as described in US2009042813, EP2044852.

In one embodiment, the further active ingredient is an antidiabetic, forexample D-tagatose.

In one embodiment, the further active ingredient is a zinc complex ofcurcumin, as described in WO2009079902.

In one embodiment, the further active ingredient is an inhibitor of the“cAMP response element binding protein” (CREB), as described inWO2009143391.

In another embodiment, the further active ingredient is an antagonist ofthe bradykinin B1 receptor, as described in WO2009124746.

In a further embodiment, the further active ingredient is a compoundwhich is capable of modulating diabetic peripheral neuropathy (DPN).Such modulators are, for example, FK-1706 or SB-509, or those asdescribed in WO1989005304, WO2009092129, WO2010002956.

In one embodiment, the further active ingredient is a compound which iscapable of modulating diabetic nephropathy. Such compounds aredescribed, for example, in WO2009089545, WO2009153261.

In one embodiment, the further active ingredient is an inhibitor (e.g.an anti-CD38 antibody) of CD38, as described in US2009196825.

In one embodiment, the further active ingredient is an inhibitor ofhuman fibroblast growth factor receptor 4 (FGFR4), as described, forexample, in WO2009046141.

In a further embodiment of the invention, the further active ingredientis a compound which protects the beta cell, for example14-alpha-lipolyl-andrographolide (AL-1).

In yet another embodiment of the invention, the further activeingredient is the INGAP (islet neogenesis associated protein) peptide, apeptide which reestablishes insulin production in patients with diabetesmellitus.

In one embodiment of the invention, the further active ingredient is amodulator of the CFTR (cystic fibrosis transmembrane conductanceregulator), as described, for example, in US2009246137, US2009264433,US2009264441, US2009264471, US2009264481, US2009264486, WO2010019239.

In one embodiment of the invention, the further active ingredient is acompound which stimulates/modulates insulin release, for example thoseas described in WO2009109258, WO2009132739, US2009281057, WO2009157418

In one embodiment of the invention, the further active ingredient is anextract from Hippophae rhamnoides, as described, for example, inWO2009125071.

In one embodiment of the invention, the further active ingredient is anfrom Huanglian and Ku Ding Cha, as described, for example, inWO2009133458.

In another embodiment, the further active ingredient is a root extractfrom Cipadessa baccifera, as described in US2009238900.

In one embodiment of the invention, the further active ingredients areborapetoside A and/or borapetoside C, which can be isolated from theplant SDH-V, a species of Tinospora crispa, as described, for example,in US2010016213.

In one embodiment, the compound of the formula I is administered incombination with bulking agents, preferably insoluble bulking agents(see, for example, Carob/Caromax® (Zunft H J; et al., Carob pulppreparation for treatment of hypercholesterolemia, ADVANCES IN THERAPY(2001 September-October), 18(5), 230-6). Caromax® is a carob-containingproduct from Nutrinova, Nutrition Specialties & Food Ingredients GmbH,Industriepark Höchst, 65926 Frankfurt/Main)). Combination with Caromax®is possible in one preparation or by separate administration ofcompounds of the formula I and Caromax®. Caromax® can in this connectionalso be administered in the form of food products such as, for example,in bakery products or muesli bars.

It will be appreciated that every suitable combination of the compoundsof the invention with one or more of the aforementioned compounds andoptionally one or more other pharmacologically active substances isconsidered to be covered within the scope of protection conferred by thepresent invention.

Also suitable are the following active ingredients for combinationpreparations:

all antiepileptics specified in the Rote Liste 2010, chapter 15;

all antihypertensives specified in the Rote Liste 2010, chapter 17;

all hypotonics specified in the Rote Liste 2010, chapter 19;

all anticoagulants specified in the Rote Liste 2010, chapter 20;

all arteriosclerosis drugs specified in the Rote Liste 2010, chapter 25;

all beta receptors, calcium channel blockers and inhibitors of the reninangiotensin system specified in the Rote Liste 2010, chapter 27;

all diuretics and perfusion-promoting drugs specified in the Rote Liste2010, chapter 36 and 37;

all withdrawal drugs/drugs for the treatment of addictive disordersspecified in the Rote Liste 2010, chapter 39;

all coronary drugs and gastrointestinal drugs specified in the RoteListe 2010, chapter 55 and 60;

all migraine drugs, neuropathy preparations and Parkinson's drugsspecified in the Rote Liste 2010, chapter 61, 66 and 70.

It will be appreciated that every suitable combination of the compoundsof the invention with one or more of the aforementioned compounds andoptionally one or more other pharmacologically active substances isconsidered to be covered within the scope of protection conferred by thepresent invention.

The examples and preparation methods adduced below serve to illustratethe invention, but without limiting it.

TABLE 1

Preparation Ex. Structure method  1

B  2

B  3

A  4

A  5

A  6

A  7

A  8

A  9

A 10

A 11

A 12

A 13

A 14

A 15

A 16

A 17

A 18

A 19

A 20

A 21

A 22

A 23

A 24

A 25

A 26

A 27

A 28

A 29

A 30

A 31

A 32

A 33

A 34

A 35

A 36

A 37

A 38

A 39

C 40

C 41

A 42

A 43

A 44

C 45

C 46

C 47

C 48

A 49

A 50

A 51

A 52

C 53

C 54

C

The efficacy of the compounds was tested as follows:

In Vitro FLIPR Assay with Recombinant Cells which Express the GPCR GPR40

Function-testing assays were performed by means of the FLIPR technique(“Fluorescence Imaging Plate Reader”, Molecular Devices Corp.). For thispurpose, agonist-induced changes were determined in the intracellularconcentration of Ca²⁺ in recombinant HEK293 cells which expressed theGPCR GPR40.

For the studies, cells were sown into 96-well microtiter plates (60 000cells/well) and left to grow overnight. The medium was removed and thecells were incubated in buffer which contains the fluorescent dyeFluo-4. After this loading with dye, the cells were washed, testsubstance was added and changes were measured in the intracellular Ca²⁺concentration in the FLIPR instrument. Results were presented as thepercentage change relative to the control (0%: no test substance added;100%: 10 μM reference agonist linoleic acid added) and used to calculatedose/effect curves, and EC₅₀ values were determined.

TABLE 2 Biological activity EC₅₀ [μM] Ex. GPR40 rat 4 0.094 5 0.176 60.071 8 1.14 9 0.553 16 0.187 22 4.46 39 5.08 40 2.13 42 10.7 43 20.8 471.16

It can be seen from the table that the compounds of the formula Iactivate the GPR40 receptor and are thus very suitable for treatment ofhyperglycemia and of diabetes. The compounds of the formula I increaseinsulin excretion (see Itoh et al., Nature 2003, 422, 173-176).

Due to the activation of the GPR40 receptor, the compounds of theformula I can also be employed for treatment or prevention of furtherdisorders.

The compounds of the present invention are especially suitable fortreatment and/or prevention of:

-   1. disorders of fatty acid metabolism and glucose utilization    disorders    -   disorders involving insulin resistance-   2. Diabetes mellitus, especially type 2 diabetes, including the    prevention of the sequelae associated therewith.    -   Particular aspects in this context are        -   hyperglycemia,        -   improvement in insulin resistance,        -   improvement in glucose tolerance,        -   protection of the pancreatic β cells        -   prevention of macro- and microvascular disorders-   3. Various other conditions which may be associated with metabolic    syndrome or syndrome X, such as    -   increased abdominal girth    -   dyslipidemia (e.g. hypertriglyceridemia and/or low HDL)    -   insulin resistance    -   hypercoagulability    -   hyperuricemia    -   microalbuminemia    -   thromboses, hypercoagulable and prothrombotic states (arterial        and venous)    -   high blood pressure    -   heart failure, for example (but not restricted to) following        myocardial infarction, hypertensive heart disease or        cardiomyopathy-   4. Memory disorders, cognitive defects, CNS disorders such as    -   age-related dementia    -   Alzheimer's disease    -   treatment of reduced attentiveness or wakefulness    -   schizophrenia        The abbreviations used stand for:        ACN acetonitrile        aq aqueous        DMF N,N-dimethylformamide        EDAC N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide        hydrochloride        ESI electrospray ionization (in MS)        h hour(s)        HOBt hydroxybenzotriazole        HPLC high-pressure, high-performance liquid chromatography        LC-MS liquid chromatography-coupled mass spectrometry        MeOH methanol        RP reverse phase        RT room temperature        THF tetrahydrofuran        TFA trifluoroacetic acid        General Preparation Methods

The inventive compounds of the formula I can be prepared according tothe following reaction schemes:

Method A:

The hydroxyacetic acid derivatives of the formula II are eithercommercially available or are obtained by reacting acetic acidderivatives of the formula V in which LG is a leaving group, for examplehalogen, tosylate or mesylate, R is an alkyl group such as methyl orethyl and R3 and R4 are each defined as described above, and the phenolsof the formula IV in which A, R5, R6 and R7 are each defined asdescribed above, in the presence of a base, for example potassiumcarbonate or cesium carbonate, in a suitable solvent, for exampledimethylformamide, tetrahydrofuran, dichloromethane or other aproticsolvents and subsequent basic hydrolysis with bases such as sodiumhydroxide or lithium hydroxide.

The hydroxyacetic acid derivatives of the formula II are reacted underthe conditions of the general amide bond syntheses, for example withEDAC, HOBtxH₂O and N-ethylmorpholine in dimethylformamide, with anilinesof the general formula VI in which R, R1, R2, R8 and R9 are each definedas described above, to give compounds of the formula VII. Subsequentbasic hydrolysis of the ester in the general formula VII gives thecompounds of the general formula I. The compounds of the general formulaI can be separated by chiral HPLC into the individual diastereomers andenantiomers Ia, Ib, Ic and Id.

Method B:

Alternatively to method A, the anilines of the general formula VIII inwhich R1, R2, R8, R9 and R are each defined as described above can bereacted with hydroxyacetic acid derivatives of the general formula IIunder the conditions of the general amide bond syntheses analogously tomethod A to give compounds of the general formula IX. The esterhydrolysis of the compounds of the general formula IX to dicarboxylicacids of the general formula X is effected under basic conditions, forexample, with sodium hydroxide or lithium hydroxide. The dicarboxylicacids of the general formula X are reacted in an inert solvent such asdioxane or toluene by decarboxylation at elevated temperatures to givecompounds of the general formula I. The compounds of the general formulaI can be separated analogously to method A into the individualdiastereomers and enantiomers Ia, Ib, Ic and Id.

Method C:

Alternatively to method A, the anilines of the general formula VI inwhich R1, R2, R8, R9 and R are each defined as described above can bereacted with the acid chlorides XI, which can be prepared from thehydroxyacetic acid derivatives of the general formula II by knownmethods, for example with thionyl chloride, with addition of base, forexample triethylamine, to give compounds of the general formula VII. Theester hydrolysis of the compounds of the general formula VII and theseparation of the compounds of the general formula I into the individualdiastereomers and enantiomers Ia, Ib, Ic and Id is effected analogouslyto method A.

Individual examples according to the different methods are described indetail hereinafter.

EXPERIMENTAL Example Synthesis According to Method A Example 13-{4-[2-(4-Bromo-2-chlorophenoxy)-2-methylpropionylamino]phenyl}hex-4-ynoicAcid

Stage 1 Dimethyl2-(1-{4-[2-(4-bromo-2-chlorophenoxy)-2-methylpropionylamino]phenyl}but-2-ynyl)malonate

To a solution of 200 mg (0.73 mmol) of dimethyl2-[1-(4-aminophenyl)but-2-ynyl]-malonate, 251 mg (2.18 mmol) ofN-ethylmorpholine, 122 mg (0.8 mmol) of HOBt hydrate and 124 mg (0.80mmol) of EDAC in 5 ml of DMF was added a solution of 213 mg (0.73 mmol)of 2-(4-bromo-2-chlorophenoxy)-2-methylpropionic acid in 3 ml of DMF.After 18 h at room temperature, another 1.1 equivalents each ofN-ethylmorpholine and HOBt hydrate were added. After 72 h, the reactionmixture was concentrated completely and separated by means ofpreparative HPLC (Merck Hibar Purospher Star RP-18e 10 μm 25×250 mm; A:H₂O+0.05% TFA; B: ACN+0.05% TFA; flow rate: 50 ml/min; in 10 minutes 10%B→80% B; in 5 minutes 80% B→90% B). The product fractions werefreeze-dried to obtain 180 mg (45%) of dimethyl2-(1-{-[2-(4-bromo-2-chlorophenoxy)-2-methylpropionylamino]phenyl}but-2-ynyl)malonate.

Stage 22-(1-{4-[2-(4-Bromo-2-chlorophenoxy)-2-methylpropionylamino]phenyl}but-2-ynyl)-malonicAcid

A solution of 180 mg of dimethyl2-(1-{4-[2-(4-bromo-2-chlorophenoxy)-2-methylpropionylamino]phenyl}but-2-ynyl)malonatein 5 ml of acetonitrile and 3.5 ml of 1 N sodium hydroxide solution (aq)was stirred at room temperature for 18 h. The reaction mixture wasadjusted to pH=1 with 1 N HCl (aq) and then extracted with ethylacetate. The organic phase was dried over MgSO₄, filtered andconcentrated under high vacuum. This gave 171 mg of2-(1-{4-[2-(4-bromo-2-chlorophenoxy)-2-methylpropionylamino]phenyl}but-2-ynyl)malonicacid in quantitative yield.

Stage 33-{4-[2-(4-Bromo-2-chlorophenoxy)-2-methylpropionylamino]phenyl}hex-4-ynoicAcid

A solution of 171 mg of2-(1-{4-[2-(4-bromo-2-chlorophenoxy)-2-methylpropionylamino]phenyl}but-2-ynyl)malonicacid in 5 ml of dioxane was boiled at 120° C. for 17 h. The reactionmixture was concentrated and separated by means of preparative HPLC(Merck Hibar Purospher Star RP-18e 10 μm 25×250 mm; A: H₂O+0.05% TFA; B:ACN+0.05% TFA; flow rate: 50 ml/min; in 15 minutes 10% B→90% B). Theproduct fractions were freeze-dried to obtain 85 mg (54%) of3-{4-[2-(4-bromo-2-chlorophenoxy)-2-methylpropionylamino]phenyl}hex-4-ynoicacid. C₂₂H₂₁BrClNO₄ (478.77), LCMS (ESI-pos): 478/480/482 (M+H⁺).

Example 2 3-{4-[2-(3-tert-Butylphenoxy)propionylamino]phenyl}hex-4-ynoicAcid

Stage 1 Dimethyl2-(1-{4-[2-(3-tert-butylphenoxy)propionylamino]phenyl}but-2-ynyl)malonate

To a solution of 250 mg (0.91 mmol) of dimethyl malonate, malonate, 314mg (2.72 mmol) of N-ethylmorpholine, 153 mg (1.0 mmol) of HOBt hydrateand 155 mg (1.0 mmol) of EDAC in 7 ml of DMF was added a solution of 202mg (0.91 mmol) of 2-(3-tert-butylphenoxy)propionic acid in 3 ml of DMF.After 18 h at room temperature, the reaction mixture was concentratedcompletely and separated by means of preparative HPLC (Merck HibarPurospher Star RP-18e 10 μm 25×250 mm; A: H₂O+0.05% TFA; B: ACN+0.05%TFA; flow rate: 50 ml/min; in 15 minutes 10% B→90% B). The productfractions were freeze-dried to give 323 mg (74%) of dimethyl2-(1-{4-[2-(3-tert-butylphenoxy)propionylamino]phenyl}but-2-ynyl)malonate.

Stage 22-(1-{4-[2-(3-tert-Butylphenoxy)propionylamino]phenyl}but-2-ynyl)malonicAcid

A solution of 323 mg (0.67 mmol) of dimethyl2-(1-{4-[2-(3-tert-butylphenoxy)-propionylamino]phenyl}but-2-ynyl)malonatein 7 ml of acetonitrile and 6.7 ml of 1 N sodium hydroxide solution (aq)was stirred at room temperature for 18 h. The reaction mixture wasadmixed with water and adjusted to pH=1 with 1 N HCl (aq) and thenextracted with ethyl acetate. The organic phase was dried over MgSO₄,filtered and concentrated under high vacuum. This gave 304 mg of2-(1-{4-[2-(3-tert-butylphenoxy)propionylamino]phenyl}but-2-ynyl)malonicacid in quantitative yield.

Stage 3 3-{4-[2-(3-tert-Butylphenoxy)propionylamino]phenyl}hex-4-ynoicacid

A solution of 304 mg (0.67 mmol) of2-(1-{4-[2-(3-tert-butylphenoxy)propionylamino]-phenyl}but-2-ynyl)malonicacid in 10 ml of dioxane was boiled at 120° C. for 27 h. The reactionmixture was concentrated and separated by means of preparative HPLC(Merck Hibar Purospher Star RP-18e 10 μm 25×250 mm; A: H₂O+0.05% TFA; B:ACN+0.05% TFA; flow rate: 50 ml/min; in 10 minutes 10% B→80% B; in 5minutes 80% B→90% B). The product fractions were freeze-dried to obtain214 mg (78%) of3-{4-[2-(3-tert-butylphenoxy)propionylamino]phenyl}hex-4-ynoic acid.C₂₅H₂₉NO₄ (407.51), LCMS (ESI-pos): 408 (M+H⁺).

Example Syntheses According to Method A Example 63-{4-[2-(3-Isopropylphenoxy)propionylamino]phenyl}hex-4-ynoic acid

Stage 1 Ethyl3-{4-[2-(3-isopropylphenoxy)propionylamino]phenyl}hex-4-ynoate

To a solution of 200 mg (0.75 mmol) of ethyl3-(4-aminophenyl)hex-4-ynoate, 258 mg (2.24 mmol) of N-ethylmorpholine,126 mg (0.82 mmol) of HOBt hydrate and 128 mg (0.82 mmol) of EDAC in 3ml of DMF was added a solution of 202 mg (0.74 mmol) of2-(3-isopropylphenoxy)propionic acid in 2.5 ml of DMF. After 72 h atroom temperature, the reaction mixture was diluted with water andextracted with ethyl acetate. The organic phase was dried over MgSO₄,filtered and concentrated under reduced pressure. This gave 156 mg ofethyl 3-{4-[2-(3-isopropylphenoxy)propionylamino]phenyl}hex-4-ynoate.

Stage 2 3-{4-[2-(3-Isopropylphenoxy)propionylamino]phenyl}hex-4-ynoicacid

A solution of 156 mg of ethyl3-{4-[2-(3-isopropylphenoxy)propionylamino]phenyl}-hex-4-ynoate in 7 mlof acetonitrile and 7 ml of 1 N NaOH (aq) was stirred at roomtemperature for 18 h. The reaction mixture was admixed with water andadjusted to pH=1 with 1 N HCl (aq) and then extracted with ethylacetate. The organic phase was dried over MgSO₄, filtered andconcentrated under high vacuum. This gave 109 mg of3-{4-[2-(3-isopropylphenoxy)propionylamino]phenyl}hex-4-ynoic acid in37% yield over the two stages.

C₂₄H₂₇NO₄ (393.49), LCMS (ESI-pos): 394 (M+H⁺).

Examples 3-9 were prepared in parallel syntheses according to thismethod.

Example 293-{4-[2-(5-Bromo-2-methylphenoxy)propionylamino]phenyl}hex-4-ynoic Acid

Stage 1 Ethyl3-{-4-[2-(5-bromo-2-methylphenoxy)propionylamino]phenyl}hex-4-ynoate

A solution of 150 mg (0.56 mmol) of ethyl 3-(4-aminophenyl)hex-4-ynoate,193 mg (1.68 mmol) of N-ethylmorpholine, 103 mg (0.67 mmol) of HOBthydrate and 104 mg (0.67 mmol) of EDAC in 3 ml of DMF was added to asolution of 160 mg (0.62 mmol) of 2-(5-bromo-2-methylphenoxy)propionicacid in 2 ml of DMF. After 3 days at room temperature, the reactionmixture was diluted with sodium chloride solution and extracted withethyl acetate. The organic phase was dried over MgSO₄, filtered andconcentrated under reduced pressure. This gave ethyl3-{4-[2-(5-bromo-2-methylphenoxy)propionylamino]phenyl}hex-4-ynoate.

Stage 23-{4-[2-(5-Bromo-2-methylphenoxy)propionylamino]phenyl}hex-4-ynoic Acid

A solution of the crude substance from stage 1 in 5 ml of acetonitrileand 10 ml of 1 N NaOH (aq) was stirred at room temperature for 22 h. Thereaction mixture was admixed with water and adjusted to pH=1 with 1 NHCl (aq) and then extracted with ethyl acetate. The organic phase wasdried over MgSO₄, filtered and concentrated under high vacuum. The crudemixture was purified by means of preparative HPLC (column: WATERSSunFire Prep 018 OBD, 5 μm, 50×100 mm; solvent A; water+0.5% TFA;solvent B: acetonitrile; flow rate 120 ml/minute, gradient: 0-2.5minutes: 75% A, 2.5-10.5 minutes: 75 to 15% A, 10.5 to 11.5 minutes: 15to 2% A). This gave 100 mg of3-{4-[2-(5-bromo-2-methylphenoxy)propionylamino]phenyl}hex-4-ynoic acidin 40% yield over the two stages.

C₂₂H₂₂BrNO₄ (444.33), LCMS (ESI-pos): 444/446 (M+H⁺).

Examples 24-31 were prepared in parallel syntheses according to thismethod.

Example 323-{4-[2-(2-Bromo-4-isopropylphenoxy)propionylamino]phenyl}-3-methoxypropionicAcid

Stage 1 Ethyl3-{4-[2-(2-bromo-4-isopropylphenoxy)propionylamino]phenyl}-3-methoxypropionate

To a solution of 150 mg (0.67 mmol) of ethyl3-(4-aminophenyl)-3-methoxypropionate, 116 mg (1.01 mmol) ofN-ethylmorpholine, 123 mg (0.81 mmol) of HOBt hydrate and 125 mg (0.81mmol) of EDAC in 2 ml of DMF was added a solution of 212 mg (0.74 mmol)of 2-(2-bromo-4-isopropylphenoxy)propionic acid in 2 ml of DMF. After 22h at room temperature, the reaction mixture was diluted with sodiumchloride solution and extracted with ethyl acetate. The organic phasewas dried over MgSO₄, filtered and concentrated under reduced pressure.This gave 331 mg of ethyl3-{4-[2-(2-bromo-4-isopropylphenoxy)propionylamino]phenyl}-3-methoxypropionate.

Stage 23-{4-[2-(2-bromo-4-isopropylphenoxy)propionylamino]phenyl}-3-methoxypropionicAcid

A solution of 331 mg of ethyl3-{4-[2-(2-bromo-4-isopropylphenoxy)propionylamino]-phenyl}-3-methoxypropionatein 7 ml of acetonitrile and 7 ml of 1 N NaOH (aq) was stirred at roomtemperature for 20 h. The reaction mixture was admixed with water andadjusted to pH=1 with 1 N HCl (aq) and then extracted with ethylacetate. The organic phase was dried over MgSO₄, filtered andconcentrated under high vacuum. The crude mixture was purified by meansof preparative HPLC (Merck Hibar Purospher Star RP-18e 10 μm 25×250 mm;A: H₂O+0.05% TFA; B: ACN+0.05% TFA; flow rate: 50 ml/min; in 10 minutes10% B→80% B; in 5 minutes 80% B→90% B). This gave 152 mg of3-{4-[2-(2-bromo-4-isopropylphenoxy)propionylamino]phenyl}-3-methoxypropionicacid in 49% yield over the two stages.

C₂₂H₂₂BrNO₄ (464.36), LCMS (ESI-pos): 432/434 ((M+H-MeOH)⁺).

Example Synthesis According to Method C Example 403-{4-[2-(2-Isopropyl-5-methylphenoxy)propionylamino]phenyl}-3-methoxypropionicAcid

Stage 1 Ethyl3-{4-[2-(2-isopropyl-5-methylphenoxy)propionylamino]phenyl}-3-methoxypropionate

A solution of 150 mg (0.67 mmol) of2-(2-isopropyl-5-methylphenoxy)propionic acid in 1 ml of thionylchloride was boiled under reflux under argon for 30 minutes. Thereaction mixture was concentrated, admixed with 2 ml of toluene andconcentrated again. The residue was dissolved in 3 ml of acetonitrileunder argon, admixed with 940 μl (0.67 mmol) of triethylamine and asolution of 150 mg (0.67 mmol) of ethyl3-(4-aminophenyl)-3-methoxypropionate and stirred at room temperaturefor 30 minutes. The reaction mixture was diluted with water, adjusted topH=6-7 with 1 N hydrochloric acid and extracted with ethyl acetate. Theorganic phase was dried over MgSO₄, filtered and concentrated under highvacuum. This gave 287 mg of ethyl3-{4-[2-(2-isopropyl-5-methylphenoxy)propionylamino]phenyl}-3-methoxypropionate.

Stage 23-{4-[2-(2-Isopropyl-5-methylphenoxy)propionylamino]phenyl}-3-methoxypropionicAcid

A solution of 287 mg (0.67 mmol) of ethyl3-{4-[2-(2-isopropyl-5-methylphenoxy)-propionylamino]phenyl}-3-methoxypropionatein 10 ml of 2N NaOH/THF/NaOH in a ratio of 1:1:1 was left to stand at RTfor 30 minutes. The reaction mixture was admixed with water and adjustedto pH=6-7 with 1 N HCl (aq) and then extracted with ethyl acetate. Theorganic phase was dried over MgSO₄, filtered and concentrated under highvacuum. The crude mixture was purified by means of preparative HPLC(Merck Hibar Purospher Star RP-18e 10 μm 25×250 mm; A: H₂O+0.05% TFA; B:ACN+0.05% TFA; flow rate: 50 ml/min; in 10 minutes 10% B→80% B; in 10minutes 80% B→90% B). This gave 138 mg of3-{4-[2-(2-isopropyl-5-methylphenoxy)propionylamino]phenyl}-3-methoxypropionicacid in 51% yield over the two stages.

C₂₃H₂₉NO₅ (399.49), LCMS (ESI-pos): 368 ((M+H-MeOH)⁺).

Example 453-Cyano-3-{4-[2-(2-isopropyl-5-methylphenoxy)propionylamino]phenyl}-propionicAcid

A solution of 164 mg (0.74 mmol) of2-(2-isopropyl-5-methylphenoxy)propionic acid in 1 ml of thionylchloride was boiled under reflux under argon for 30 minutes. Thereaction mixture was concentrated, admixed with 2 ml of toluene andconcentrated again. The residue was dissolved in 5 ml of acetonitrileunder argon, 200 mg of tert-butyl 3-(4-aminophenyl)-3-cyanopropionatewere added and the mixture was reacted at room temperature for 4 days.The reaction mixture was concentrated under high vacuum and purifiedtwice by means of preparative HPLC (Merck Hibar Purospher Star RP-18e 10μm 25×250 mm; A: H₂O+0.05% TFA; B: ACN+0.05% TFA; flow rate: 50 ml/min;first separation: in 10 minutes 10% B→80% B; in 5 minutes 80% B→90% B,second separation: 2 minutes 5% B; in 27 minutes 5% B→100% B; 5 minutes100% B). The combined clean fractions were freeze-dried and gave 74 mgof tert-butyl3-cyano-3-{4-[2-(2-isopropyl-5-methylphenoxy)propionylamino]phenyl}-propionateand 144 mg (45%) of3-cyano-3-{4-[2-(2-isopropyl-5-methylphenoxy)-propionylamino]phenyl}propionicacid.

C₂₃H₂₆N₂O₄ (394.47), LCMS (ESI-pos): 395 ((M+H)⁺).

All other examples were synthesized analogously to the preparationprocess specified in the table. The compounds were analyzed by means ofLC/MS. The corresponding molecular peak or the elimination products (seeexamples) was detected by LC/MS in all examples.

The invention claimed is:
 1. A compound of the formula I

in which R1 is O—(C₁-C₆)-alkyl, O—(C₃-C₆)-cycloalkyl,O—(C₁-C₃)-alkylene-(C₃-C₆)-cycloalkyl, —(C₂-C₆)-alkynyl or CN, where theO—(C₁-C₆)-alkyl radical, the O—(C₃-C₆)-cycloalkyl, theO—(C₁-C₃)-alkylene-(C₃-C₆)-cycloalkyl and the (C₂-C₆)-alkynyl radicalmay be mono- or polysubstituted by F; R2, R9 is H, F, Cl, Br, CN, CH₃,CO—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl or O—(C₁-C₆)-alkyl, where theCO—(C₁-C₆)-alkyl radical, the (C₁-C₆)-alkyl radical and theO—(C₁-C₆)-alkyl radical may each be mono- or polysubstituted by F; R3 isH, (C₁-C₆)-alkyl, (C₁-C₃)-alkylene-(C₃-C₆)-cycloalkyl or(C₃-C₆)-cycloalkyl; R4 is (C₁-C₆)-alkyl,(C₁-C₃)-alkylene-(C₃-C₆)-cycloalkyl or (C₃-C₆)-cycloalkyl; R5, R6, R7are each independently H, F, Cl, Br, I, NO₂, CN, O—(C₁-C₆)-alkyl,(C₁-C₆)-alkyl, (C₁-C₃)-alkylene-(C₃-C₆)-cycloalkyl, NH₂,NH(C₁-C₆)-alkyl, N((C₁-C₆)-alkyl)₂, SO₂—CH₃, SO₂—NH₂,SO₂—NH(C₁-C₆)-alkyl, SO₂—N((C₁-C₆)-alkyl)₂, COOH, COO—(C₁-C₆)—alkyl,CONH₂, CONH(C₁-C₆)-alkyl, CON((C₁-C₆)-alkyl)₂, SF₅, (C₆-C₁₀)-aryl,(C₃-C₁₀)-cycloalkyl, or a 4- to 12-membered heterocycle, where the(C₁-C₆)-alkyl radical and the O—(C₁-C₆)-alkyl radical may be mono- orpolysubstituted by F and where the (C₆-C₁₀)-aryl radical, the(C₃-C₁₀)-cycloalkyl radical and the 4- to 12-membered heterocycleradical may each be mono- to trisubstituted by F, Cl, Br, I, OH, CF₃,CHF₂, CH₂F, NO₂, CN, OCF₃, OCHF₂, O—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, NH₂,NH(C₁-C₆)-alkyl, N((C₁-C₆)-alkyl)₂, SO₂—CH₃, SO₂—NH₂,SO₂—NH(C₁-C₆)-alkyl, SO₂—N((C₁-C₆)-alkyl)₂, COOH, COO—(C₁-C₆)-alkyl,CONH₂, CONH(C₁-C₆)-alkyl, CON((C₁-C₆)-alkyl)₂ or SF₅; R8 is H or(C₁-C₆)-alkyl; A is (C₆-C₁₀)-aryl or a 4- to 12-membered heterocycle;and physiologically compatible salts thereof.
 2. The compound as claimedin claim 1, wherein R1 is O—(C₁-C₆)-alkyl, O—(C₃-C₆)-cycloalkyl,O—(C₁-C₃)-alkylene-(C₃-C₆)-cycloalkyl, —(C₂-C₆)-alkynyl or CN, where theO—(C₁-C₆)-alkyl radical, the O—(C₃-C₆)-cycloalkyl, theO—(C₁-C₃)-alkylene-(C₃-C₆)-cycloalkyl and the (C₂-C₆)-alkynyl radicalmay be mono- or polysubstituted by F; R2, R9 is H, F, Cl, Br, CN, CH₃,CO—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl or O—(C₁-C₆)-alkyl, where theCO—(C₁-C₆)-alkyl radical, the (C₁-C₆)-alkyl radical and theO—(C₁-C₆)-alkyl radical may each be mono- or polysubstituted by F; R3 isH, (C₁-C₆)-alkyl, (C₁-C₃)-alkylene-(C₃-C₆)-cycloalkyl or(C₃-C₆)-cycloalkyl; R4 is (C₁-C₆)-alkyl,(C₁-C₃)-alkylene-(C₃-C₆)-cycloalkyl or (C₃-C₆)-cycloalkyl; R5, R6, R7are each independently H, F, Cl, Br, I, CN, O—(C₁-C₆)-alkyl,(C₁-C₆)-alkyl, SF₅ or phenyl, where the (C₁-C₆)-alkyl radical and theO—(C₁-C₆)-alkyl radical may each be mono- or polysubstituted by F; R8 isH or (C₁-C₆)-alkyl; A is phenyl or a 6-membered heterocycle; andphysiologically compatible salts thereof.
 3. The compound as claimed inclaim 1, wherein R1 is O—(C₁-C₆)-alkyl or —(C₂-C₆)-alkynyl, where theO—(C₁-C₆)-alkyl radical and the (C₂-C₆)-alkynyl radical may be mono- orpolysubstituted by F; R2, R9 is H; R3 is H, (C₁-C₆)-alkyl,(C₁-C₃)-alkylene-(C₃-C₆)-cycloalkyl or (C₃-C₆)-cycloalkyl; R4 is(C₁-C₆)-alkyl, (C₁-C₃)-alkylene-(C₃-C₆)-cycloalkyl or(C₃-C₆)-cycloalkyl; R5, R6, R7 are each independently H, Cl, Br, CH₃ or(C₁-C₆)-alkyl, where the (C₁-C₆)-alkyl radical may be mono- orpolysubstituted by F; R8 is H; A is phenyl or pyridyl; andphysiologically compatible salts thereof.
 4. The compound as claimed inclaim 1, wherein R1 is O—(C₁-C₆)-alkyl, where the O—(C₁-C₆)-alkylradical may be mono- or polysubstituted by F; R2, R9 is H; R3 is H,(C₁-C₆)-alkyl, (C₁-C₃)-alkylene-(C₃-C₆)-cycloalkyl or(C₃-C₆)-cycloalkyl; R4 is (C₁-C₆)-alkyl,(C₁-C₃)-alkylene-(C₃-C₆)-cycloalkyl or (C₃-C₆)-cycloalkyl; R5, R6, R7are each independently H, Cl, Br, CH₃ or (C₁-C₆)-alkyl, where the(C₁-C₆)-alkyl radical may be mono- or polysubstituted by F; R8 is H; Ais phenyl or pyridyl; and physiologically compatible salts thereof. 5.The compound as claimed in claim 1, wherein R1 is —(C₂-C₆)-alkynyl,where the (C₂-C₆)-alkynyl radical may be mono- or polysubstituted by F;R2, R9 is H; R3 is H, (C₁-C₆)-alkyl, (C₁-C₃)-alkylene-(C₃-C₆)-cycloalkylor (C₃-C₆)-cycloalkyl; R4 is (C₁-C₆)-alkyl,(C₁-C₃)-alkylene-(C₃-C₆)-cycloalkyl or (C₃-C₆)-cycloalkyl; R5, R6, R7are each independently H, Cl, Br, CH₃ or (C₁-C₆)-alkyl, where the(C₁-C₆)-alkyl radical may be mono- or polysubstituted by F; R8 is H; Ais phenyl or pyridyl; and physiologically compatible salts thereof.
 6. Apharmaceutical composition comprising one or more compounds as claimedin claim
 1. 7. The pharmaceutical composition as claimed in claim 6,which comprises at least one further active ingredient.
 8. Thepharmaceutical composition as claimed in claim 7, which comprises, as afurther active ingredient, one or more antidiabetics, activehypoglycemic ingredients, HMG-CoA reductase inhibitors, cholesterolabsorption inhibitors, PPAR gamma agonists, PPAR alpha agonists, PPARalpha/gamma agonists, PPAR delta agonists, fibrates, MTP inhibitors,bile acid absorption inhibitors, CETP inhibitors, polymeric bile acidadsorbers, LDL receptor inducers, ACAT inhibitors, antioxidants,lipoprotein lipase inhibitors, ATP citrate lyase inhibitors, squalenesynthetase inhibitors, lipoprotein(a) antagonists, HM74A receptoragonists, lipase inhibitors, insulins, sulfonylureas, biguanides,meglitinides, thiazolidinediones, α-glucosidase inhibitors, activeingredients which act on the ATP-dependent potassium channel of the betacells, glycogen phosphorylase inhibitors, glucagon receptor antagonists,activators of glucokinase, inhibitors of gluconeogenesis, inhibitors offructose 1,6-biphosphatase, modulators of glucose transporter 4,inhibitors of glutamine fructose-6-phosphate amidotransferase,inhibitors of dipeptidylpeptidase IV, inhibitors of11-beta-hydroxysteroid dehydrogenase 1, inhibitors of protein tyrosinephosphatase 1B, modulators of the sodium-dependent glucose transporter 1or 2, inhibitors of hormone-sensitive lipase, inhibitors of acetyl-CoAcarboxylase, inhibitors of phosphoenolpyruvate carboxykinase, inhibitorsof glycogen synthase kinase-3 beta, inhibitors of protein kinase C beta,endothelin-A receptor antagonists, inhibitors of I kappaB kinase,modulators of the glucocorticoid receptor, CART agonists, NPY agonists,MC4 agonists, orexin agonists, H3 agonists, TNF agonists, CRF agonists,CRF BP antagonists, urocortin agonists, β3 agonists, CB1 receptorantagonists, MSH (melanocyte-stimulating hormone) agonists, CCKagonists, serotonin reuptake inhibitors, mixed serotoninergic andnoradrenergic compounds, 5HT agonists, bombesin agonists, galaninantagonists, growth hormones, growth hormone-releasing compounds, TRHagonists, decoupling protein 2 or 3 modulators, leptin agonists, DAagonists, lipase/amylase inhibitors, PPAR modulators, RXR modulators orTR-β-agonists or amphetamines.
 9. The pharmaceutical composition asclaimed in claim 7, which comprises, as a further active ingredient,metformin, arcabose, glibenclamide, glimepiride, gliclazide, gliquidone,pioglitazone, rosiglitazone, exenatide, miglitol, vildagliptin,sitagliptin, repaglinide, nateglinide or mitiglinide.
 10. Thepharmaceutical composition as claimed in claim 7 which comprises, as afurther active ingredient, lixisenatide.
 11. A method for lowering bloodglucose in a patient in need thereof comprising administering to saidpatient a therapeutically effective amount of the pharmaceuticalcomposition of claim
 1. 12. A method for treating diabetes in a patientin need thereof comprising administering to said patient atherapeutically effective amount of the pharmaceutical composition ofclaim
 1. 13. A method for increasing insulin excretion in a patient inneed thereof comprising administering to said patient a therapeuticallyeffective amount of the pharmaceutical composition of claim
 1. 14. Aprocess for preparing a pharmaceutical composition comprising one ormore of the compounds as claimed in claim 1, comprising mixing an activeingredient with a pharmaceutically suitable carrier and converting saidmixture to a form suitable for administration.
 15. A kit composed ofseparate packages of a) an effective amount of the compound of theformula I as claimed in claim 1, and b) an effective amount of a furthermedicinal active ingredient.